Bicyclic pyrimidine and pyrimidine derivatives useful as anticancer agents

ABSTRACT

The invention relates to compounds of the formulas 1 and 2                  
 
and to prodrugs thereof, pharmaceutically acceptable salts or solvates of said compounds or said prodrugs, wherein X, R 1  and R 11  are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formulas 1 and 2 and to methods of treating hyperproliferative disorders in a mammal by administering the compounds of formulas 1 and 2.

This application claims benefit to international application No.PCT/US02/19830, filed on Jun. 20, 2002, published in English, whichclaims the benefit of U.S. provisional application No. 60/299,879, filedon Jun. 21, 2001.

BACKGROUND OF THE INVENTION

This invention relates to novel bicyclic pyridine and pyrimidinederivatives that are useful in the treatment of hyperproliferativediseases, such as cancers, in mammals. This invention also relates to amethod of using such compounds in the treatment of hyperproliferativediseases in mammals, especially humans, and to pharmaceuticalcompositions containing such compounds.

Compounds that are useful in the treatment of hyperproliferativediseases are also disclosed in the following patents and applications:PCT international patent application publication number WO 00/38665(published Jul. 6, 2001), PCT international patent applicationpublication number WO 97/49688 (published Dec. 31, 1997), PCTinternational patent application publication number WO 98/23613(published Jun. 4, 1998), U.S. patent application Ser. No. 08/953,078(filed Oct. 17, 1997), U.S. Pat. No. 6,071,935 issued Jun. 6, 2000, PCTinternational patent application publication number WO 96/30347(published Oct. 3, 1996), PCT international patent applicationpublication number WO 96/40142 (published Dec. 19,1996), PCTinternational patent application publication number WO 97/13771(published Apr. 17, 1997), and PCT international patent applicationpublication number WO 95/23141 (published Aug. 31, 1995). The foregoingpatent and applications are incorporated herein by reference in theirentirety.

It is known that a cell may become cancerous by virtue of thetransformation of a portion of its DNA into an oncogene (i.e. a genethat upon activation leads to the formation of malignant tumor cells).Many oncogenes encode proteins which are aberrant tyrosine kinasescapable of causing cell transformation. Alternatively, theoverexpression of a normal proto-oncogenic tyrosine kinase may alsoresult in proliferative disorders, sometimes resulting in a malignantphenotype.

Receptor tyrosine kinases are large enzymes that span the cell membraneand possess an extracellular binding domain for growth factors such asepidermal growth factor, a transmembrane domain, and an intracellularportion that functions as a kinase to phosphorylate a specific tyrosineresidue in proteins and hence to influence cell proliferation. Theforegoing tyrosine kinases may be classified as growth factor receptor(e.g. EGFR, PDGFR, FGFR and erbB2) or non-receptor (e.g. c-src andbcr-abl) kinases. It is known that such kinases are often aberrantlyexpressed in common human cancers such as breast cancer,gastrointestinal cancer such as colon, rectal or stomach cancer,leukemia, and ovarian, bronchial or pancreatic cancer. Aberrant erbB2activity has been implicated in breast, ovarian, non-small cell lung,pancreatic, gastric and colon cancers. It has also been shown thatepidermal growth factor receptor (EGFR) is mutated or overexpressed inmany human cancers such as brain, lung, squamous cell, bladder, gastric,breast, head and neck, oesophageal, gynecological and thyroid cancers.Thus, it is believed that inhibitors of receptor tyrosine kinases, suchas the compounds of the present invention, are useful as selectiveinhibitors of the growth of mammalian cancer cells.

It has also been shown that EGFR inhibitors may be useful in thetreatment of pancreatitis and kidney disease (such as proliferativeglomerulonephritis and diabetes-induced renal disease), and may reducesuccessful blastocyte implantation and therefore may be useful as acontraceptive. See PCT international application publication number WO95/19970 (published Jul. 27, 1995).

It is known that polypeptide growth factors such as vascular endothelialgrowth factor (VEGF) having a high affinity to the human kinaseinsert-domain-containing receptor (KDR) or the murine fetal liver kinase1 (FLK-1) receptor have been associated with the proliferation ofendothelial cells and more particularly vasculogenesis and angiogenesis.See PCT international application publication number WO 95/21613(published Aug. 17, 1995). Agents, such as the compounds of the presentinvention, that are capable of binding to or modulating the KDR/FLK-1receptor may be used to treat disorders related to vasculogenesis orangiogenesis such as diabetes, diabetic retinopathy, hemangioma, glioma,melanoma, Kaposi's sarcoma and ovarian, breast, lung, pancreatic,prostate, colon and epidermoid cancer.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the formulas 1 and 2

and to prodrugs thereof, pharmaceutically acceptable salts or solvatesof said compounds and said prodrugs,

wherein X is CH or N;

R¹ is H, C₁–C₆ alkyl, —C(O)(C₁–C₆ alkyl), C₆–C₁₀ aryl or 5 to 13membered heterocyclic, wherein said C₆–C₁₀ aryl and 5 to 13 memberedheterocyclic groups are optionally substituted by 1 to 5 R⁵substituents;

each R⁵ is independently selected from halo, cyano, nitro,trifluoromethoxy, trifluoromethyl, azido, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —NR⁶C(O)R⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —OR⁹, —SO₂NR⁶R⁷, C₁–C₆ alkyl,—(CH₂)_(j)O(CH₂)_(q)NR⁶R⁷, —(CH₂)_(t)O(CH₂)_(q)OR⁹, —(CH₂)_(t)OR⁹,—S(O)_(j)(C₁–C₆ alkyl), —(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to 10membered heterocyclic), —C(O)(CH₂)_(t)(C₆–C₁₀ aryl),—(CH₂)_(t)O(CH₂)_(j)(C₆–C₁₀ aryl), —(CH₂)_(t)O(CH₂)_(q)(5 to 10 memberedheterocyclic), —C(O)(CH₂)_(t)(5 to 10 membered heterocyclic),—(CH₂)_(j)NR⁷(CH₂)_(q)NR⁸R⁷, —(CH₂)_(j)NR⁷CH₂C(O)NR⁶R⁷,—(CH₂)_(j)NR⁷(CH₂)_(q)NR⁹C(O)R⁸, —(CH₂)_(j)NR⁷(CH₂)_(t)O(CH₂)_(q)OR⁹,—(CH₂)_(j)NR⁷(CH₂)_(q)S(O)_(j)(C₁–C₆ alkyl), —(CH₂)_(j)NR⁷(CH₂)_(t)R⁶,—SO₂(CH₂)_(t)(C₆–C₁₀ aryl), and —SO₂(CH₂)_(t)(5 to 10 memberedheterocyclic), wherein j is an integer from 0 to 2, t is an integer from0 to 6, q is an integer from 2 to 6, the —(CH₂)_(q)— and —(CH₂)_(t)—moieties of the foregoing R⁵ groups optionally include a carbon-carbondouble or triple bond where t is an integer between 2 and 6, and thealkyl, aryl and heterocyclic moieties of the foregoing R⁵ groups areoptionally substituted by 1 to 3 substituents independently selectedfrom halo, cyano, nitro, trifluoromethyl, azido, —C(O)R⁸, —C(O)OR⁸,—OC(O)R⁸, —OC(O)OR⁸, —NR⁶C(O)R⁷, —C(O)NR⁶R⁷, —(CH₂)_(t)NR⁶R⁷, C₁–C₆alkyl, —(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to 10 memberedheterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹, and —(CH₂)_(t)OR⁹, wherein t isan integer from 0 to 6 and q is an integer from 2 to 6;

each R⁶ and R⁷ is independently selected from H, C₁–C₆ alkyl,—(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to 10 membered heterocyclic),—(CH₂)_(t)O(CH₂)_(q)OR⁹, and —(CH₂)_(t)OR⁹, wherein t is an integer from0 to 6 and q is an integer from 2 to 6, and the alkyl, aryl andheterocyclic moieties of the foregoing R⁶ and R⁷ groups are optionallysubstituted by 1 to 3 substituents independently selected from halo,cyano, nitro, trifluoromethyl, azido, —C(O)R⁸, —C(O)OR⁸, —CO(O)R⁸,—OC(O)OR⁸, —NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰, —NR⁹R¹⁰, C₁–C₆ alkyl,—(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to 10 membered heterocyclic),—(CH₂)_(t)O(CH₂)_(q)OR⁹, and —(CH₂)_(t)OR⁹, wherein t is an integer from0 to 6 and q is an integer from 2 to 6, with the proviso that where R⁶and R⁷ are both attached to the same nitrogen, then R⁶ and R⁷ are notboth bonded to the nitrogen directly through an oxygen;

each R⁸ is independently selected from H, C₁–C₁₀ alkyl,—(CH₂)_(t)(C₆–C₁₀ aryl), and —(CH₂)_(t)(5 to 10 membered heterocyclic),wherein t is an integer from 0 to 6;

each R⁹ and R¹⁰ is independently selected from H and C₁–C₆ alky; and,

R¹¹ is H, C₁–C₆ alky, —C(O)NR¹²R¹³, —C(O)(C₆–C₁₀ aryl),—(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to 10 membered heterocyclic),—(CH₂)_(t)NR¹²R¹³, —SO₂NR¹²R¹³ and —CO₂R¹², wherein t is an integer from0 to 6, wherein said R¹¹ groups C₁–C₆ alkyl, —C(O)(C₆–C₁₀ aryl),—(CH₂)_(t)(C₆–C₁₀ aryl), and —(CH₂)_(t)(5 to 10 membered heterocyclic)are optionally substituted by 1 to 5 R⁵ groups, and wherein each R¹² andR¹³ is independently selected from H, C₁–C₆ alkyl, —(CH₂)_(t)(C₃–C₁₀cycloalkyl), —(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to 10 memberedheterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹, and —(CH₂)_(t)OR⁹, q is aninteger from 2 to 6, and the alkyl, aryl and heterocyclic moieties ofthe foregoing R¹² and R¹³ groups are optionally substituted by 1 to 3substituents independently selected from R⁵ or R¹² and R¹³ are takentogether with the nitrogen to which they are attached to form a C₅–C₉azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, ordihydroisoquinolinyl ring, wherein said C₅–C₉ azabicyclic, aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring, and saidrings are optionally substituted by 1 to 5 R⁵ substituents, with theproviso R¹² and R¹³ are not both bonded to the nitrogen directly throughan oxygen.

In one preferred embodiment of the compound of formula 1 R¹¹ is—(CH₂)_(t)(5 to 10 membered heterocyclic), —C(O)NR¹²R¹³,—(CH₂)_(t)NR¹²R¹³, —SO₂NR¹²R¹³ and —CO₂R¹², wherein t is an integer from0 to 6, wherein said R¹¹ group —(CH₂)_(t)(5 to 10 membered heterocyclic)is optionally substituted by 1 to 5 R⁵ groups and wherein each R¹² andR¹³ is independently selected from H, C₁–C₈ alkyl, —(CH₂)_(t)(C₃–C₁₀cycloalkyl), —(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to 10 memberedheterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹, —(CH₂)_(t)OR⁹, q is an integerfrom 2 to 6, and the alkyl, aryl and heterocyclic moieties of theforegoing R¹² and R¹³ groups are optionally substituted by 1 to 3substituents independently selected from R⁵ or R¹² and R¹³ are takentogether with the nitrogen to which they are attached to form a C₅–C₉azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, ordihydroisoquinolinyl ring, wherein said C₅–C₉ azabicyclic, aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring areoptionally substituted by 1 to 5 R⁵ substituents, with the proviso R¹²and R¹³ are not both bonded to the nitrogen directly through an oxygen.

In another preferred embodiment of the compound of formula 1 R¹¹ is—(CH₂)_(t)(5 to 10 membered heterocyclic), —C(O)NR¹²R¹³, —SO₂NR¹²R¹³ and—CO₂R¹², wherein t is an integer from 0 to 6, wherein said R¹¹ group—(CH₂)_(t)(5 to 10 membered heterocyclic) is optionally substituted by 1to 5 R⁵ groups and wherein each R¹² and R¹³ is independently selectedfrom H, C₁–C₆ alkyl, —(CH₂)_(t)(C₃–C₁₀ cycloalkyl), —(CH₂)_(t)(C₆–C₁₀aryl), —(CH₂)_(t)(5 to 10 membered heterocyclic),—(CH₂)_(t)O(CH₂)_(q)OR⁹, —(CH₂)_(t)OR⁹, q is an integer from 2 to 6, andthe alkyl, aryl and heterocyclic moieties of the foregoing R¹² and R¹³groups are optionally substituted by 1 to 3 substituents independentlyselected from R⁵ or R¹² and R¹³ are taken together with the nitrogen towhich they are attached to form a C₅–C₉ azabicyclic, aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring, whereinsaid C₅–C₉ azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl,or dihydroisoquinolinyl ring are optionally substituted by 1 to 5 R⁵substituents, with the proviso R¹² and R¹³ are not both bonded to thenitrogen directly through an oxygen.

In another preferred embodiment of the compound of formula 1 R¹¹ is—(CH₂)_(t)(5 to 10 membered heterocyclic), and —C(O)NR¹²R¹³, wherein tis an integer from 0 to 6, wherein said R¹¹ group —(CH₂)_(t)(5 to 10membered heterocyclic) is optionally substituted by 1 to 5 R⁵ groups andwherein each R¹² and R¹³ is independently selected from H, C₁–C₆ alkyl,—(CH₂)_(t)(C₃–C₁₀ cycloalkyl), —(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to10 membered heterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹, —(CH₂)_(t)OR⁹, q isan integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties ofthe foregoing R¹² and R¹³ groups are optionally substituted by 1 to 3substituents independently selected from R⁵ or R¹² and R¹³ are takentogether with the nitrogen to which they are attached to form a C₅–C₉azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, ordihydroisoquinolinyl ring, wherein said C₅–C₉ azabicyclic, aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring areoptionally substituted by 1 to 5 R⁵ substituents, with the proviso R¹²and R¹³ are not both bonded to the nitrogen directly through an oxygen.

In another preferred embodiment of the compound of formula 1 R¹¹ is—C(O)NR¹²R¹³, wherein R¹² and R¹³ are independently selected from H,C₁–C₆ alkyl, —(CH₂)_(t)(C₃–C₁₀ cycloalkyl), —(CH₂)_(t)(C₆–C₁₀ aryl),—(CH₂)_(t)(5 to 10 membered heterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹,—(CH₂)_(t)OR⁹, wherein t is an integer from 0 to 6, q is an integer from2 to 6, and the alkyl, aryl and heterocyclic moieties of the foregoingR¹² and R¹³ groups are optionally substituted by 1 to 3 substituentsindependently selected from R⁵ or R¹² and R¹³ are taken together withthe nitrogen to which they are attached to form a C₅–C₉ azabicyclic,aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinylring, wherein said C₅–C₉ azabicyclic, aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,isoquinolinyl, or dihydroisoquinolinyl ring are optionally substitutedby 1 to 5 R⁵ substituents, with the proviso R¹² and R¹³ are not bothbonded to the nitrogen directly through an oxygen.

In another preferred embodiment of the compound of formula 1 R¹¹ is—C(O)NR¹²R¹³, wherein R¹² and R¹³ are taken together with the nitrogento which they are attached to form a C₅–C₉ azabicyclic, aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring, whereinsaid C₅–C₉ azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl,or dihydroisoquinolinyl ring are optionally substituted by 1 to 5 R⁵substituents.

In another preferred embodiment of the compound of formula 1 R¹¹ is—C(O)NR¹²R¹³ wherein R¹² and R¹³ are taken together with the nitrogen towhich they are attached to form a pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, ordihydroisoquinolinyl ring, wherein said pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, ordihydroisoquinolinyl ring are optionally substituted by 1 to 5 R⁵substituents.

In another preferred embodiment of the compound of formula 1 R¹¹ is—C(O)NR¹²R¹³, wherein R¹² and R¹³ are taken together with the nitrogento which they are attached to form a pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, or thiomorpholinyl ring, wherein saidpyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiomorpholinylring are optionally substituted by 1 to 5 R⁵ substituents.

In another preferred embodiment of the compound of formula 1 R¹¹ is—C(O)NR¹²R¹³, wherein R¹² and R¹³ are taken together with the nitrogento which they are attached to form a pyrrolidinyl or piperidinyl ring,wherein said pyrrolidinyl or piperidinyl ring are optionally substitutedby 1 to 5 R⁵ substituents.

In another preferred embodiment of the compound of formula 1 R¹¹ is—C(O)NR¹²R¹³ wherein R¹² and R¹³ are taken together with the nitrogen towhich they are attached to form a pyrrolidinyl ring, wherein saidpyrrolidinyl is optionally substituted by 1 to 5 R⁵ substituents.

In another preferred embodiment of the compound of formula 1 R¹¹ is—C(O)NR¹²R¹³, wherein R¹² and R¹³ are taken together with the nitrogento which they are attached to form a pyrrolidin-1-yl ring, wherein saidpyrrolidin-1-yl is optionally substituted by 1 to 5 R⁵ substituents.

In another preferred embodiment of the compound of formula 1 R¹¹ is—(CH₂)_(t)(5 to 10 membered heterocyclic) group, wherein t is an integerfrom 0 to 6, said —(CH₂)_(t)(5 to 10 membered heterocyclic) group isoptionally substituted by 1 to 5 R⁵ groups.

In another preferred embodiment of the compound of formula 1 R¹¹ is—(CH₂)_(t)(5–8 membered heterocyclic) group, wherein t is an integerfrom 0 to 6, said —(CH₂)_(t)(5–8 membered heterocyclic) group isoptionally substituted by 1 to 5 R⁵ groups.

In another preferred embodiment of the compound of formula 1 R¹¹ is—(CH₂)_(t)(5 or 6 membered heterocyclic) group, wherein t is an integerfrom 0 to 6, said —(CH₂)_(t)(5 or 6 membered heterocyclic) group isoptionally substituted by 1 to 5 R⁵ groups.

In another preferred embodiment of the compound of formula 1 R¹¹ is—(CH₂)_(t)(5 membered heterocyclic) group, wherein t is an integer from0 to 6, said —(CH₂)_(t)(5 membered heterocyclic) group is optionallysubstituted by 1 to 5 R⁵ groups.

In another e preferred embodiment the compound of formula 1 R¹¹ is—(CH₂)_(t)thiazolyl, wherein t is an integer from 0 to 6, said—(CH₂)_(t)thiazolyl is optionally substituted by 1 to 5 R⁵ groups.

Other preferred compounds include those of formula 1 wherein R¹ isphenyl optionally substituted by 1 to 5 R⁵ substituents, or R¹ is agroup of the formula

wherein X² is —S— or —N(R⁶)—, X³ is N or CH, the dashed line in formula3 represents an optional double bond, and the above R¹ groups offormulas 3 and 5 are optionally substituted by 1 to 5 R⁵ substituentsand the R¹ groups of formulas 4 and 6 are optionally substituted by 1 to3 R⁵ substituents. Specifically preferred compounds include thosewherein R¹ is a group of formula 3 above wherein said group isoptionally substituted by 1 to 5 R⁵ substituents.

Specific embodiments of the present invention include the followingcompounds:

-   (3R)-(3-methoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;-   (3S)-(3-Methoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;-   (3R,4R)-(3,4-Dimethoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;-   meso-(3,4-Dimethoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;-   (3S,4S)-(3,4-Dimethoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;-   (R)-(2-Hydroxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;-   (S)-(2-Hydroxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;-   (2R)-(2-Methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;-   (2S)-(2-Methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;-   (R)-[7-(1-Ethyl-2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-(2-methoxymethyl-pyrrolidin-1-yl)-methanone;-   (2R)-[7-(1,2-Dimethyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-(2-methoxymethyl-pyrrolidin-1-yl)-methanone;-   (2R)-1-{5-[2-(2-Methoxymethyl-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-indol-1-yl}-ethanone;-   (2R)-[7-(1-Methanesulfonyl-2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-(2-methoxymethyl-pyrrolidin-1-yl)-methanone;-   2-(3-Methyl-3H-imidazol-4-yl)-7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine;-   2-(1-Methyl-1H-imidazol-2-yl)-7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine;-   2-{2-[7-(2-Methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-4-yl}-propan-2-ol;-   2-{2-[7-(2-Methyl-quinolin-6-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-4-yl}-propan-2-ol;-   2-{2-[7-(Quinolin-6-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-4-yl}-propan-2-ol;-   2-{2-[7-(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-4-yl}-propan-2-ol;-   {4-Methyl-2-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-4-methyl-piperazin-1-yl)-methanone;-   2-Methyl-5-{2-[4-methyl-5-(4-methyl-piperazine-1-carbonyl)-thiazol-2-yl]-thieno[3,2-b]pyridin-7-yloxy}-1H-indole-3-carbonitrile;-   {4-Methyl-2-[7-(5-phenyl-1H-pyrazol-3-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-morpholin-4-yl-methanone;-   (2-{7-[5-(4-Fluoro-phenyl)-1H-pyrazol-3-yloxy]-thieno[3,2-b]pyridin-2-yl}-4-methyl-thiazol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;-   2-{(7-[5-(4-Methoxy-phenyl)-1H-pyrazol-3-yloxy]-thieno[3,2-b]pyridin-2-yl}-4-methyl-thiazol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;    and pharmaceutically acceptable salts and solvates of said    compounds.

The present invention also relates to intermediate compounds of theformulas 25 and 26

and to pharmaceutically acceptable salts thereof, wherein:

Z¹ is halo, —CO₂H, —CONH₂, —CSNH₂ and Z² is —OR¹; or

Z¹ is R¹¹ and Z² is halo; or

Z¹ and Z² are each independently halo;

X is N or CH; and wherein R¹ and R¹¹ are as defined for said compoundsof formulas 1 and 2.

The above intermediates of formulas 25 and 26 may be used to prepare theabove compounds of formulas 1 and 2.

This invention also relates to pharmaceutical compositions containingand methods for treating abnormal cell growth through administeringprodrugs of compounds of the formulas 1 and 2. Compounds of formulas 1and 2 having free amino, amido, hydroxy or carboxylic groups can beconverted into prodrugs.

The invention also relates to a pharmaceutical composition for thetreatment of a hyperproliferative disorder in a mammal which comprises atherapeutically effective amount of a compound of formula 1 or 2, orprodrugs thereof, pharmaceutically acceptable salts or solvates of saidcompounds and said prodrugs, and a pharmaceutically acceptable carrier.In one embodiment, said pharmaceutical composition is for the treatmentof cancer such as brain, lung, squamous cell, bladder, gastric,pancreatic, breast, head, neck, renal, kidney, ovarian, prostate,colorectal, oesophageal, gynecological or thyroid cancer. In anotherembodiment, said pharmaceutical composition is for the treatment of anon-cancerous hyperproliferative disorder such as benign hyperplasia ofthe skin (e.g., psoriasis) or prostate (e.g., benign prostatichypertropy (BPH)).

The invention also relates to a pharmaceutical composition for thetreatment of pancreatitis or kidney disease (including proliferativeglomerulonephritis and diabetes-induced renal disease) in a mammal whichcomprises a therapeutically effective amount of a compound of formula 1or 2, or prodrugs thereof, pharmaceutically acceptable salts or solvatesof said compounds and said prodrugs, and a pharmaceutically acceptablecarrier.

The invention also relates to a pharmaceutical composition for theprevention of blastocyte implantation in a mammal which comprises atherapeutically effective amount of a compound of formula 1 or 2, orprodrugs thereof, pharmaceutically acceptable salts or solvates of saidcompounds and said prodrugs, and a pharmaceutically acceptable carrier.

The invention also relates to a pharmaceutical composition for treatinga disease related to vasculogenesis or angiogenesis in a mammal whichcomprises a therapeutically effective amount of a compound of formula 1or 2, or prodrugs thereof, pharmaceutically acceptable salts or solvatesof said compounds and said prodrugs, and a pharmaceutically acceptablecarrier. In one embodiment, said pharmaceutical composition is fortreating a disease selected from the group consisting of tumorangiogenesis, chronic inflammatory disease such as rheumatoid arthritis,atherosclerosis, skin diseases such as psoriasis, excema, andscleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity,age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi'ssarcoma and ovarian, breast, lung, pancreatic, prostate, colon andepidermoid cancer.

The invention also relates to a method of treating a hyperproliferativedisorder in a mammal which comprises administering to said mammal atherapeutically effective amount of the compound of formula 1 or 2, orprodrugs thereof, pharmaceutically acceptable salts or solvates of saidcompounds and said prodrugs. In one embodiment, said method relates tothe treatment of cancer such as brain, squamous cell, bladder, gastric,pancreatic, breast, head, neck, oesophageal, prostate, colorectal, lung,renal, kidney, ovarian, gynecological or thyroid cancer. In anotherembodiment, said method relates to the treatment of a non-canceroushyperproliferative disorder such as benign hyperplasia of the skin(e.g., psoriasis) or prostate (e.g., benign prostatic hypertropy (BPH)).

The invention also relates to a method for the treatment of ahyperproliferative disorder in a mammal which comprises administering tosaid mammal a therapeutically effective amount of a compound of formula1 or 2, or prodrugs thereof, pharmaceutically acceptable salts orsolvates of said compounds and said prodrugs, in combination with ananti-tumor agent selected from the group consisting of mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,and anti-androgens.

The invention also relates to a method of treating pancreatitis orkidney disease in a mammal which comprises administering to said mammala therapeutically effective amount of a compound of formula 1 or 2, orprodrugs thereof, pharmaceutically acceptable salts or solvates of saidcompounds and said prodrugs.

The invention also relates to a method of preventing blastocyteimplantation in a mammal which comprises administering to said mammal atherapeutically effective amount of a compound of formula 1 or 2, orprodrugs thereof, pharmaceutically acceptable salts or solvates of saidcompounds and said prodrugs.

The invention also relates to a method of treating diseases related tovasculogenesis or angiogenesis in a mammal which comprises administeringto said mammal an effective amount of a compound of formula 1 or 2, orprodrugs thereof, pharmaceutically acceptable salts or solvates of saidcompounds and said prodrugs. In one embodiment, said method is fortreating a disease selected from the group consisting of tumorangiogenesis, chronic inflammatory disease such as rheumatoid arthritis,atherosclerosis, skin diseases such as psoriasis, excema, andscleroderma, diabetes, diabetic retinopathy, retinopathy of prematurity,age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi'ssarcoma and ovarian, breast, lung, pancreatic, prostate, colon andepidermoid cancer.

Patients that can be treated with the compounds of formulas 1 and 2, andprodrugs thereof, pharmaceutically acceptable salts or solvates of saidcompounds and said prodrugs, according to the methods of this inventioninclude, for example, patients that have been diagnosed as havingpsoriasis, BPH, lung cancer, bone cancer, pancreatic cancer, skincancer, cancer of the head and neck, cutaneous or intraocular melanoma,uterine cancer, ovarian cancer, rectal cancer, cancer of the analregion, stomach cancer, colon cancer, breast cancer, gynecologic tumors(e.g., uterine sarcomas, carcinoma of the fallopian tubes, carcinoma ofthe endometrium, carcinoma of the cervix, carcinoma of the vagina orcarcinoma of the vulva), Hodgkin's disease, cancer of the esophagus,cancer of the small intestine, cancer of the endocrine system (e.g.,cancer of the thyroid, parathyroid or adrenal glands), sarcomas of softtissues, cancer of the urethra, cancer of the penis, prostate cancer,chronic or acute leukemia, solid tumors of childhood, lymphocyticlymphonas, cancer of the bladder, cancer of the kidney or ureter (e.g.,renal cell carcinoma, carcinoma of the renal pelvis), or neoplasms ofthe central nervous system (e.g., primary CNS lymphona, spinal axistumors, brain stem gliomas or pituitary adenomas).

This invention also relates to a pharmaceutical composition forinhibiting abnormal cell growth in a mammal, including a human,comprising an amount of a compound of the formula 1 or 2 as definedabove, or prodrug thereof, pharmaceutically acceptable salt or solvateof said compound and said prodrug, that is effective in inhibitingfarnesyl protein transferase, and a pharmaceutically acceptable carrier.

This invention also relates to a pharmaceutical composition forinhibiting abnormal cell growth in a mammal which comprises an amount ofa compound of formula 1 or 2, or prodrug thereof, pharmaceuticallyacceptable salt or solvate of said compound and said prodrug, incombination with an amount of a chemotherapeutic, wherein the amounts ofthe compound, salt, solvate, or prodrug, and of the chemotherapeutic aretogether effective in inhibiting abnormal cell growth. Manychemotherapeutics are presently known in the art. In one embodiment, thechemotherapeutic is selected from the group consisting of mitoticinhibitors, alkylating agents, anti-metabolites, intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes,topoisomerase inhibitors, biological response modifiers, anti-hormones,e.g. anti-androgens.

This invention further relates to a method for inhibiting abnormal cellgrowth in a mammal which method comprises administering to the mammal anamount of a compound of formula 1 or 2, or prodrug thereof,pharmaceutically acceptable salt or solvate of said compound and saidprodrug, in combination with radiation therapy, wherein the amount ofthe compound, salt, solvate or prodrug is in combination with theradiation therapy effective in inhibiting abnormal cell growth in themammal. Techniques for administering radiation therapy are known in theart, and these techniques can be used in the combination therapydescribed herein. The administration of the compound of the invention inthis combination therapy can be determined as described herein.

It is believed that the compounds of formula 1 or 2 can render abnormalcells more sensitive to treatment with radiation for purposes of killingand/or inhibiting the growth of such cells. Accordingly, this inventionfurther relates to a method for sensitizing abnormal cells in a mammalto treatment with radiation which comprises administering to the mammalan amount of a compound of formula 1 or 2 or prodrug thereof,pharmaceutically acceptable salt or solvate of said compound and saidprodrug, which amount is effective in sensitizing abnormal cells totreatment with radiation. The amount of the compound, salt, solvate orprodrug in this method can be determined according to the means forascertaining effective amounts of such compounds described herein.

This invention also relates to a method of and to a pharmaceuticalcomposition for inhibiting abnormal cell growth in a mammal whichcomprises an amount of a compound of formula 1 or 2, or prodrug thereof,pharmaceutically acceptable salt or solvate of said compound and saidprodrug, or an isotopically-labelled derivative thereof, and an amountof one or more substances selected from anti-angiogenesis agents, signaltransduction inhibitors, and antiproliferative agents.

Anti-angiogenesis agents, such as MMP-2 (matrix-metalloproteinase 2)inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX-II(cyclooxygenase II) inhibitors, can be used in conjunction with acompound of formula 1 or 2 and pharmaceutical compositions describedherein. Examples of useful COX-II inhibitors include CELEBREX™(alecoxib), valdecoxib, and rofecoxib. Examples of useful matrixmetalloproteinase inhibitors are described in WO 96/33172 (publishedOct. 24, 1996), WO 96/27583 (published Mar. 7, 1996), European PatentApplication No. 97304971.1 (filed Jul. 8, 1997), European PatentApplication No. 99308617.2 (filed Oct. 29, 1999), WO 98/07697 (publishedFeb. 26, 1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998), WO98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul. 16,1998), European Patent Publication 606,046 (published Jul. 13, 1994),European Patent Publication 931,788 (published Jul. 28, 1999), WO90/05719 (published May 31, 1990), WO 99/52910 (published Oct. 21,1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667 (publishedJun. 17, 1999), PCT International Application No. PCT/IB98/01113 (filedJul. 21, 1998), European Patent Application No. 99302232.1 (filed Mar.25, 1999), Great Britain patent application number 9912961.1 (filed Jun.3, 1999), U.S. Provisional Application No. 60/148,464 (filed Aug. 12,1999), U.S. Pat. No. 5,863,949 (issued Jan. 26, 1999), U.S. Pat. No.5,861,510 (issued Jan. 19, 1999), and European Patent Publication780,386 (published Jun. 25, 1997), all of which are incorporated hereinin their entireties by reference. Preferred MMP-2 and MMP-9 inhibitorsare those that have little or no activity inhibiting MMP-1. Morepreferred, are those that selectively inhibit MMP-2 and/or MMP-9relative to the other matrix-metalloproteinases (i.e. MMP-1, MMP-3,MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

Some specific examples of MMP inhibitors useful in the present inventionare Prinomastat (AG-3340), RO 32-3555, RS 13-0830, and the compoundsrecited in the following list

-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl)-amino]-propionic    acid;-   3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide;-   (2R,3R)1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic    acid hydroxyamide;-   4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic    acid hydroxyamide;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-amino]-propionic    acid;-   4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxylic    acid hydroxyamide;-   (R)3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxylic    acid hydroxyamide;-   (2R,3R)1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-piperidine-2-carboxylic    acid hydroxyamide;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-ethyl)-amino]-propionic    acid;-   3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro-pyran-4-yl)-amino]-propionic    acid;-   3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide;-   3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]octane-3-carboxylic    acid hydroxyamide; and-   (R)    3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxylic    acid hydroxyamide;-   and pharmaceutically acceptable salts and solvates of said    compounds.

Other anti-angiogenesis agents, including other COX-II inhibitors andother MMP inhibitors, can also be used in the present invention.

A compound of formula 1 or 2, can also be used with signal transductioninhibitors, such as agents that can inhibit EGFR (epidermal growthfactor receptor) responses, such as EGFR antibodies, EGF antibodies, andmolecules that are EGFR inhibitors; VEGF (vascular endothelial growthfactor) inhibitors, such as VEGF receptors and molecules that caninhibit VEGF; and erbB2 receptor inhibitors, such as organic moleculesor antibodies that bind to the erbB2 receptor, for example, HERCEPTIN™(Genentech, Inc. of South San Francisco, Calif., USA).

EGFR inhibitors are described in, for example in WO 95/19970 (publishedJul. 27, 1995), WO 98/14451 (published Apr. 9,1998), WO 98/02434(published Jan. 22, 1998), and U.S. Pat. No. 5,747,498 (issued May 5,1998), and such substances can be used in the present invention asdescribed herein. EGFR-inhibiting agents include, but are not limitedto, the monoclonal antibodies C225 and anti-EGFR 22Mab (ImClone SystemsIncorporated of New York, N.Y., USA), the compounds ZD-1839(AstraZeneca), BIBX-1382 (Boehringer Ingelheim), MDX-447 (Medarex Inc.of Annandale, N.J., USA), and OLX-103 (Merck & Co. of WhitehouseStation, N.J., USA), VRCTC-310 (Ventech Research) and EGF fusion toxin(Seragen Inc. of Hopkinton, Mass.). These and other EGFR-inhibitingagents can be used in the present invention.

VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen Inc. of SouthSan Francisco, Calif., USA), can also be combined with the compound ofthe present invention. VEGF inhibitors are described in, for example inWO 99/24440 (published May 20, 1999), PCT International ApplicationPCT/IB99/00797 (filed May 3, 1999), in WO 95/21613 (published Aug. 17,1995), WO 99/61422 (published Dec. 2, 1999), U.S. Pat. No. 5,834,504(issued Nov. 10, 1998), WO 98/50356 (published Nov. 12, 1998), U.S. Pat.No. 5,883,113 (issued Mar. 16, 1999), U.S. Pat. No. 5,886,020 (issuedMar. 23, 1999), U.S. Pat. No. 5,792,783 (issued Aug. 11, 1998), WO99/10349 (published Mar. 4, 1999), WO 97/32856 (published Sep. 12,1997), WO 97/22596 (published Jun. 26, 1997), WO 98/54093 (publishedDec. 3, 1998), WO 98/02438 (published Jan. 22, 1998), WO 99/16755(published Apr. 8, 1999), and WO 98/02437 (published Jan. 22, 1998), allof which are incorporated herein in their entireties by reference. Otherexamples of some specific VEGF inhibitors useful in the presentinvention are IM862 (Cytran Inc. of Kirkland, Wash., USA); anti-VEGFmonoclonal antibody of Genentech, Inc. of South San Francisco, Calif.;and angiozyme, a synthetic ribozyme from Ribozyme (Boulder, Colo.) andChiron (Emeryville, Calif.). These and other VEGF inhibitors can be usedin the present invention as described herein.

ErbB2 receptor inhibitors, such as GW-282974 (Glaxo Wellcome plc), andthe monoclonal antibodies AR-209 (Aronex Pharmaceuticals Inc. of TheWoodlands, Tex., USA) and 2B-1 (Chiron), can furthermore be combinedwith the compound of the invention, for example those indicated in WO98/02434 (published Jan. 22, 1998), WO 99/35146 (published Jul. 15,1999), WO 99/35132 (published Jul. 15, 1999), WO 98/02437 (publishedJan. 22, 1998), WO 97/13760 (published Apr. 17, 1997), WO 95/19970(published Jul. 27, 1995), U.S. Pat. No. 5,587,458 (issued Dec. 24,1996), and U.S. Pat. No. 5,877,305 (issued Mar. 2, 1999), which are allhereby incorporated herein in their entireties by reference. ErbB2receptor inhibitors useful in the present invention are also describedin U.S. Provisional Application No. 60/117,341, filed Jan. 27, 1999, andin U.S. Provisional Application No. 60/117,346, filed Jan. 27, 1999,both of which are incorporated in their entireties herein by reference.The erbB2 receptor inhibitor compounds and substance described in theaforementioned PCT applications, U.S. patents, and U.S. provisionalapplications, as well as other compounds and substances that inhibit theerbB2 receptor, can be used with the compounds of the present invention.

The compounds of the invention can also be used with other agents usefulin treating abnormal cell growth or cancer, including, but not limitedto, agents capable of enhancing antitumor immune responses, such asCTLA4 (cytotoxic lymphocyte antigen 4) antibodies, and other agentscapable of blocking CTLA4; and anti-proliferative agents such as otherfarnesyl protein transferase inhibitors, and the like. Specific CTLA4antibodies that can be used in the present invention include thosedescribed in U.S. Provisional Application 60/113,647 (filed Dec. 23,1998) which is incorporated by reference in its entirety, however otherCTLA4 antibodies can be used in the present invention.

The subject invention also includes isotopically-labelled compounds,which are identical to those recited in formula 1 or 2, but for the factthat one or more atoms are replaced by an atom having an atomic mass ormass number different from the atomic mass or mass number usually foundin nature. Examples of isotopes that can be incorporated into compoundsof the invention include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Compounds of thepresent invention, prodrugs thereof, and pharmaceutically acceptablesalts of said compounds or of said prodrugs which contain theaforementioned isotopes and/or other isotopes of other atoms are withinthe scope of this invention. Certain isotopically-labelled compounds ofthe present invention, for example those into which radioactive isotopessuch as ³H and ¹⁴C are incorporated, are useful in drug and/or substratetissue distribution assays. Tritiated, i.e., ³H, and carbon-14, i.e.,¹⁴C, isotopes are particularly preferred for their ease of preparationand detectability. Further, substitution with heavier isotopes such asdeuterium, i.e., ²H, can afford certain therapeutic advantages resultingfrom greater metabolic stability, for example increased In vivohalf-life or reduced dosage requirements and, hence, may be preferred insome circumstances. Isotopically labelled compounds of formula 1 or 2 ofthis invention and prodrugs thereof can generally be prepared bycarrying out the procedures disclosed in the Schemes and/or in theExamples below, by substituting a readily available isotopicallylabelled reagent for a non-isotopically labelled reagent.

The compounds of formula 1 or 2 and their pharmaceutically acceptablesalts and solvates can each independently also furthermore be used in apalliative neo-adjuvant/adjuvant therapy in alleviating the symptomsassociated with the diseases recited herein as well as the symptomsassociated with abnormal cell growth. Such therapy can be a monotherapyor can be in a combination with chemotherapy and/or immunotherapy.

The terms “abnormal cell growth” and “hyperproliferative disorder” areused interchangeably in this application.

“Abnormal cell growth”, as used herein, refers to cell growth that isindependent of normal regulatory mechanisms (e.g., loss of contactinhibition), including the abnormal growth of normal cells and thegrowth of abnormal cells. This includes, but is not limited to, theabnormal growth of: (1) tumor cells (tumors), both benign and malignant,expressing an activated Ras oncogene; (2) tumor cells, both benign andmalignant, in which the Ras protein is activated as a result ofoncogenic mutation in another gene; (3) benign and malignant cells ofother proliferative diseases in which aberrant Ras activation occurs.Examples of such benign proliferative diseases are psoriasis, benignprostatic hypertrophy, human papilloma virus (HPV), and restinosis.“Abnormal cell growth” also refers to and includes the abnormal growthof cells, both benign and malignant, resulting from activity of theenzyme farnesyl protein transferase.

The term “treating”, as used herein, unless otherwise indicated, meansreversing, alleviating, inhibiting the progress of, or preventing thedisorder or condition to which such term applies, or one or moresymptoms of such disorder or condition. The term “treatment”, as usedherein, refers to the act of treating, as “treating” is definedimmediately above.

The term “halo”, as used herein, unless otherwise indicated, meansfluoro, chloro, bromo or iodo. Preferred halo groups are fluoro, chloroand bromo.

The term “alkyl”, as used herein, unless otherwise indicated, meanssaturated monovalent hydrocarbon radicals having straight, cyclic orbranched moieties. Said “alkyl” group may include an optionalcarbon-carbon double or triple bond where said alkyl group comprises atleast two carbon atoms. It is understood that for cyclic moieties atleast three carbon atoms are required in said alkyl group.

The term “alkoxy”, as used herein, unless otherwise indicated, meansO-alkyl groups wherein “alkyl” is as defined above.

The term “aryl”, as used herein, unless otherwise indicated, means anorganic radical derived from an aromatic hydrocarbon by removal of onehydrogen, such as phenyl or naphthyl.

The terms “5 membered heterocyclic”, “5 or 6 membered heterocyclic”, “5to 8 membered heterocyclic”, “5 to 10 membered heterocyclic” or “5 to 13membered heterocyclic”, as used herein, unless otherwise indicated,includes aromatic and non-aromatic heterocyclic groups containing one tofour heteroatoms each selected from O, S and N, wherein eachheterocyclic group has from 5, 6, 5 to 8, 5 to 10 or 5 to 13 atoms inits ring system. The heterocyclic groups include benzo-fused ringsystems and ring systems substituted with one or two oxo (═O) moietiessuch as pyrrolidin-2-one. An example of a 5 membered heterocyclic groupis thiazolyl, an example of a 10 membered heterocyclic group isquinolinyl, and an example of a 13 membered heterocyclic group is acarbazole group. Examples of non-aromatic heterocyclic groups arepyrrolidinyl, piperidino, morpholino, thiomorpholino and piperazinyl.Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl,pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl,thienyl, isoxazolyl and thiazolyl. Heterocyclic groups having a fusedbenzene ring include benzimidazolyl, benzofuranyl, andbenzo[1,3]dioxolyl.

The phrase “pharmaceutically acceptable salt(s)”, as used herein, unlessotherwise indicated, means salts of acidic or basic groups which may bepresent in the compounds or prodrugs of formulas 1 and 2. The compoundsand prodrugs of formulas 1 and 2 that are basic in nature are capable offorming a wide variety of salts with various inorganic and organicacids. The acids that may be used to prepare pharmaceutically acceptableacid addition salts of such basic compounds and prodrugs of formulas 1and 2 are those that form non-toxic acid addition salts, i.e. saltscontaining pharmacologically acceptable anions, such as thehydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate,phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate,citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate,succinate, maleate, gentsinate, fumarate, gluconate, glucaronate,saccharate, formate, benzoate, glutamate, methanesulfonate,ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate)] salts.

Those compounds and prodrugs of the formulas 1 and 2 that are acidic innature, are capable of forming base salts with various pharmacologicallyacceptable cations. Examples of such salts include the alkali metal oralkaline earth metal salts and particularly, the sodium and potassiumsalts.

The compounds of the present invention may have asymmetric carbon atoms.Such diasteromeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods known to those skilled in the art, for example, bychromatography or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixtures into a diasteromericmixture by reaction with an appropriate optically active compound (e.g.,alcohol), separating the diastereomers and converting (e.g.,hydrolyzing) the individual diastereomers to the corresponding pureenantiomers. All such isomers, including diastereomer mixtures and pureenantiomers are considered as part of the invention.

The compounds of present invention may in certain instances exist astautomers. This invention relates to the use of all such tautomers andmixtures thereof.

The term “prodrug”, as used herein, unless otherwise indicated, meanscompounds that are drug precursors, which following administration,release the drug in vivo via some chemical or physiological process(e.g., a prodrug on being brought to the physiological pH is convertedto the desired drug form).

Prodrugs include compounds wherein an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues is covalently joined through an amide or ester bond to a freeamino, hydroxy or carboxylic acid group of compounds of formulas 1 and2. The amino acid residues include but are not limited to the 20naturally occurring amino acids commonly designated by three lettersymbols and also includes 4-hydroxyproline, hydroxylysine, demosine,isodemosine, 3-methylhistidine, norvalin, beta-alanine,gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithineand methionine sulfone. Additional types of prodrugs are alsoencompassed. For instance, free carboxyl groups can be derivatized asamides or alkyl esters. Free hydroxy groups may be derivatized usinggroups including but not limited to hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, as outlinedin Advanced Drug Delivery Reviews, 1996, 19, 115. Carbamate prodrugs ofhydroxy and amino groups are also included, as are carbonate prodrugs,sulfonate esters and sulfate esters of hydroxy groups. Derivatization ofhydroxy groups as (acyloxy)methyl and (acyloxy)ethyl ethers wherein theacyl group may be an alkyl ester, optionally substituted with groupsincluding but not limited to ether, amine and carboxylic acidfunctionalities, or where the acyl group is an amino acid ester asdescribed above, are also encompassed. Prodrugs of this type aredescribed in J. Med. Chem. 1996, 39, 10. Free amines can also bederivatized as amides, sulfonamides or phosphonamides. All of theseprodrug moieties may incorporate groups including but not limited toether, amine and carboxylic acid functionalities.

It will be appreciated that any solvate (e.g. hydrate) form of compoundsof formulas 1 and 2 and prodrugs thereof can be used for the purpose ofthe present invention.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention are prepared using the followingthienopyridine and thienopyrimidine synthetic intermediates:

The examples of the present invention employ the7-chloro-thieno[3,2-b]-pyridine as a synthetic intermediate. Methods toprepare the following regiosiomers, 4-chloro-thieno[2,3-b]pyridine,4-chloro-thieno[3,2-d]pyrimidine and 4-chloro-thieno[2,3-d]pyrimidine assynthetic intermediates are well known to those skilled in the art. Forexample, the regioisomer 4-chloro-thieno[2,3-b]pyridine may be preparedin the manner described in Klemm, L. H.; Hartling, R.; J. Heterocycl.Chem. 1976 13(6), pages 1197–1200, which is hereby incorporated in itsentirety by reference. The syntheses of regioisomers4-chloro-thieno[3,2-d]pyrimidine and 4-chloro-thieno[2,3-d]pyrimidineare described in U.S. Pat. No. 5,654,307, which is hereby incorporatedin its entirety by reference. Accordingly, the synthetic intermediate7-chloro-thieno[3,2-b]-pyridine employed in the examples and schemes ofthe present invention can be readily substituted by any of theregioisomeric synthetic intermediates, 4-chloro-thieno[2,3-b]pyridine,4-chloro-thieno[3,2-d]pyrimidine and 4-chloro-thieno[2,3-d]pyrimidine.

The preparation of the compounds of the present invention is illustratedin Schemes 1–5 and described below.

The compounds of the present invention are readily prepared according tosynthetic methods familiar to those skilled in the art. Scheme 1illustrates a general synthetic procedure for preparing the compounds ofthe present invention. The compound of formula 7, in which X is CH or N,may be prepared by one or more procedures described in published PCTinternational applications numbers WO 95/19774 (published Jul. 27,1995), WO 95/19970 (published Jul. 27, 1995), and WO 97/13771 (publishedApr. 17, 1997). In addition, 4-chlorothieno[3,2-d]pyrimidine iscommercially available from Maybridge Chemical Co. Ltd, Cornwall,England. A preferred method of preparing 4-chlorothieno[3,2-d]pyridineis described below with reference to steps 1–3 of Scheme 2.

In step 1 of Scheme 1, the compound of formula 7 may be converted to thecorresponding carboxy derivative of formula 8 by treating the startingcompound, for example, with lithium diisopropylamine or n-butyllithium,and then carbon dioxide gas in a non-polar solvent, such astetrahydrofuran (THF), at a temperature of about −78° C. for a period ofabout 15 minutes to one-half hour and then gradually warming the mixtureto room temperature (20–25° C).

In step 2 of Scheme 1, the compound of formula 8 may be coupled with acompound of formula HOR¹, wherein R¹ is as defined above, optionally inthe presence of a base, such as cesium carbonate, pyridine,triethylamine or sodium hydride, under an inert atmosphere, such as drynitrogen gas, in a solvent, such as a C₁–C₆ alcohol, dimethylformamide(DMF), 1,2-dichloroethane (DCE), N-methylpyrrolidin-2-one (NMP),chloroform, acetonitrile, tetrahydrofuran (THF), dimethylsulfoxide(DMSO), 1,4-dioxane or pyridine, or a mixture of two or more of theforegoing solvents, preferably a mixture of t-butyl alcohol and DCE, ata temperature of from ambient to reflux temperature, preferably 80–125°C., for a period of about 2 hours to 72 hours to provide the compound offormula 9.

Where the compound of formula HOR¹ is an optionally substituted indoleor indoline moiety, such compounds can be prepared according to one ormore methods known to those skilled in the art. Such methods aredescribed in PCT international patent application publication number WO95/23141, referred to above, and in W. C. Sumpter and F. M. Miller,“Heterocyclic Compounds with Indole and Carbazole Systems,” in volume 8of “The Chemistry of Heterocyclic Compounds”, Interscience PublishersInc., New York (1954). Where the compound of formula HOR¹ is anoptionally substituted quinoline, isoquinoline, or quinazolinederivative, such compounds can also be prepared according to one or moremethods known to those skilled in the art. Such methods are described inA. R. Katrizky, C. W. Rees, and E. F. V. Scriven, “ComprehensiveHeterocyclic Chemistry II”, volumes 5, 6, and 7, Elsevier Science Ltd.,Oxford (1996). Optional substituents can be included as appropriatebefore or after the coupling step illustrated in Scheme 1. Prior to thecoupling step, hydroxy and primary and secondary amino moieties (otherthan said hydroxy of formula HOR¹) are preferably protected using anitrogen protecting group known to those skilled in the art. Suchprotecting groups and their use are described in T. W. Greene and P. G.M. Wuts, “Protective Groups in Organic Synthesis,” Second Edition, JohnWiley & Sons, New York, 1991.

In step 3 of Scheme 1, transformation of the carboxy derivative offormula 9 to the compound of formula 1 is carried out using standardsynthetic methods well known to those of ordinary skill in the art, suchas described in B. S. Furniss, A. J. Hannaford, P. W. G. Smith and A. R.Tatchell, “Vogel's Textbook of Practical Organic Chemistry,” FifthEdition, Longman, Harlow, England, 1996. Optional substituents on theR¹¹ group can be included as appropriate using methods well known tothose of ordinary skill in the art, before or after step 3 of Scheme 1.

In the alternative, steps 2 and 3 of Scheme 1 may be reversed. That is,the R¹¹ group may be introduced into the compound of formula prior tothe addition of HOR¹ as described above.

Scheme 2 illustrates a procedure for preparing the compounds of formula16 wherein X is CH. In step 1 of Scheme 2, the compound of formula 10(3-amino-thiophene-2-carboxylic acid methyl ester) is dissolved insodium hydroxide and refluxed for about 2 hours. The solution is thencooled to 0° C. and acidified to pH 5 with concentrated HCl at whichtime a precipitate will form. The precipitate is separated and treatedwith propanol and oxalic acid, and the solution is stirred at about 38°C. for approximately 45 minutes to provide the compound of formula 11(thiophen-3-ylamine). In step 2 of Scheme 2, the compound of formula 11is dissolved in triethyl orthoformate and stirred at room temperatureuntil dissolution is complete. 2,2-Dimethyl-[1,3]dioxane-4,6-dione isthen added portionwise at room temperature, with a precipitate formingupon completion of the addition. The mixture is then heated at 85° C.overnight. The resulting precipitate,(2,2-dimethyl-5-(thiophen-3-ylaminomethylene)-[1,3]dioxane-4,6-dione),is then separated and washed. The intermediate is added to dowtherm A(heated to 260° C.), and the resulting mixture is heated for 30 minutesand then cooled to room temperature to provide the compound of formula12. In step 3 of Scheme 2, the compound of formula 12 is added to oxalylchloride in a mixture of methylene chloride and DMF and heated to refluxfor approximately two hours to provide the compound of formula 13. Thecompound of formula 13 may be converted to the compound of formula 14 asdescribed above with respect to step 1 of Scheme 1. The compound offormula 14 may be converted to the compound of formula 15 as describedabove with respect to step 2 of Scheme 1. The compound of formula 15 maybe converted to the compound of formula 16 as described above withrespect to step 3 of Scheme 1.

In order to make a compound of formula 1 wherein R¹¹ is —C(O)NR¹²R¹³,the compound of formula 15 is coupled, for example, with HNR¹²R¹³ usingcoupling methods well known to those of ordinary skill in the art andfound, for example, in PCT international application number WO 94/07910,which is incorporated herein by reference in its entirety.Alternatively, the compound of formula 14 can be transformed into theacid chloride derivative by treating it with oxalyl or thionyl chloridein dichloromethane at room temperature for 2–4 hours. The resulting acidchloride is then treated with a compound of formula HNR¹²R¹³ to providethe desired compound of formula 1 wherein R¹¹ is an amide derivative.

A compound of formula 1 wherein R¹¹ is a sulfonyl derivative can beprepared by treating a compound of formula 7 as described in step 1 ofScheme 1, with sulfonyl or sulfonamidyl halide in place of carbondioxide.

When the R¹¹ substituent of formula 1 is linked through an amino group,transformation of the carboxy group of compound 8 to the amino group isfirst required. This can be accomplished using the Curtius reaction,wherein the acid chloride derivative of compound 8 is treated with, forexample, sodium azide, and the resulting acyl azide is allowed todecompose in the presence of acid to afford the amino derivative. Theresulting amino compound can be further functionalized by acylating witha variety of carboxylic acids, acid chlorides, sulfonic acids, sulfonylchlorides, or guanylating agents to produce a variety of R¹¹ groups,such as, —NR¹²C(═O)R¹³, —NR⁹SO₂R¹², —NR⁹SO₂NR¹²R¹³, —NR⁹C(═NR¹²)R¹³,and—NR⁹C(═NR¹²)NR⁹R¹³.

Scheme 3 illustrates a second general synthetic procedure for preparingthe compounds of the present invention. In step 1 of Scheme 3, thecompound of formula 7 may be converted to the corresponding bromoderivative of formula 17 by treating the starting compound with lithiumdiisopropylamine or n-butyllithium, and then1,2-dibromo-1,1,2,2-tetrafluoroethane or bromine in a non-polar solvent,such as tetrahydrofuran CRHF), at a temperature of about −78° C. for aperiod of about 15 minutes to one-half hour and then gradually warmingthe mixture to room temperature (20–25° C.).

In step 2 of Scheme 3, the compound of formula 17 may be coupled with acompound of formula HOR¹, wherein R¹ is as defined above, optionally inthe presence of a base, such as cesium carbonate, pyridine,triethylamine or sodium hydride, under an inert atmosphere, such as drynitrogen gas, in a solvent, such as a t-butyl alcohol, dimethylformamide(DMF), 1,2-dichloroethane (DCE), N-methylpyrrolidin-2-one (NMP),chloroform, acetonitrile, tetrahydrofuran (THF), dimethylsulfoxide(DMSO), 1,4-dioxane or pyridine, or a mixture of two or more of theforegoing solvents, preferably a mixture of t-butyl alcohol and DCE, ata temperature of from ambient to reflux temperature, preferably 80–125°C., for a period of about 2 hours to 72 hours to provide the compound offormula 18. The foregoing reaction is preferably done in a sealed tube.

In step 3 of Scheme 3, the compound of formula 18 may be converted tothe compound of formula 1 by coupling the starting compound with acompound of the formula R¹¹—B(OH)₂ (wherein R¹¹ is as defined above) inthe presence of 1,4-bis(diphenylphosphino)butane and a palladiumcatalyst, such as bis(benzonitrile)-palladium(II) chloride, a base, suchas sodium or potassium carbonate, and a solvent, such as toluene,ethanol, THF, DMF, or dimethoxyethane (DME), preferably a mixture oftoluene, ethanol and THF, at a temperature within the range of about50–110° C. for a period of about 1 to 24 hours. This step is analogousto the Suzuki coupling procedure described in N. Miyaura, A. Suzuki,Chem. Rev. 1995, 95, 2457.

In the alternative, steps 2 and 3 of Scheme 3 may be reversed. That is,the R¹¹ group may be introduced into the compound of formula 7 followedby the coupling of the resulting compound with the compound of formulaHOR¹ as described above.

In another procedure, step 3 of Scheme 3 may be achieved by reacting thecompound of formula 18 with a compound of the formula(trialkylstannyl)-R¹¹ (wherein R¹¹ is as defined above), such as(tributylstannyl)-R¹¹, in the presence of copper iodide andtrans-benzyl(chloro)bis(triphenylphosphine)palladium(II) in DMF at atemperature of about 90° C. for a period of about 14 hours. The startingcompound for this procedure, specifically (tributylstannyl)-R¹¹, may beprepared from R¹¹—Br by at least three separate procedures. In a firstprocedure, R¹¹—Br may be treated with (tributylstannyl)-chloride andn-butyllithium in THF or DMF to provide (tributylstannyl)-R¹¹. In asecond procedure, R¹¹—Br may be treated with Bu₃Sn—SnBu₃, wherein Burepresents butyl, and sodium metal to provide (tributylstannyl)-R¹¹. Andin a third procedure, R¹¹—Br may be treated with Bu₃Sn—SnBu₃, wherein Burepresents butyl, and Pd(PPh₃)₄, wherein Ph represents phenyl, intoluene to provide (tributylstannyl)-R¹¹.

Following or before step 3 of Scheme 3, the R¹¹ group may be modified tointroduce one or more R⁵ groups (wherein R⁵ is as defined above). In aone preferred method, where R¹¹ is a heteroaryl group that includes analdehyde group, the aldehyde may be converted to a preferred aminomethylgroup. In this process, the starting compound that includes an aldehydeon the R¹¹ group is reacted with an amine of the formula HNR⁶R⁷ (whereinR⁶ and R⁷ are as defined above) in the presence of a reducing agent,such as sodium cyanoborohydride or sodium borohydride, in a solventcomprising acetic acid and ethanol or methanol at a temperature in therange of 0–100° C., preferably room temperature. This process convertsthe aldehyde to a moiety of the formula R⁶R⁷NCH₂—.”) Other methods ofmodifying the compounds of formula 1 will be obvious to those skilled inthe art.

Scheme 4 illustrates a procedure for preparing the compounds of formula1 wherein X is CH and R¹¹ is substituted imidiazole. The compound offormula 19 is prepared as described in WO 99/2440, hereby incorporatedby reference.

Scheme 5 illustrates a procedure for preparing the compounds of formula1 wherein X is CH and R¹¹ is substituted thiazole. The preparation ofthe compound of formula 22 is described in Example 16. Thiazolecompounds of formula 23 can be prepared by combining compound 22 withalpha-halo aldehydes or ketones under the conditions described in A. R.Katrizky and C. W. Rees, “Comprehensive Heterocyclic Chemistry”, volume6, chapter 4.19, Pergamon Press, Oxford (1984). Optional substituentscan be included as appropriate before or after the introduction of theintroduction of the compound HOR¹ in step 3 of Scheme 5.

The compounds of formulas 1 and 2 that are basic in nature are capableof forming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate the compound of formula 1 or 2 from the reactionmixture as a pharmaceutically unacceptable salt and then simply convertthe latter back to the free base compound by treatment with an alkalinereagent and subsequently convert the latter free base to apharmaceutically acceptable acid addition salt. The acid addition saltsof the base compounds of this invention are readily prepared by treatingthe base compound with a substantially equivalent amount of the chosenmineral or organic acid in an aqueous solvent medium or in a suitableorganic solvent, such as methanol or ethanol. Upon careful evaporationof the solvent, the desired solid salt is readily obtained. The desiredacid salt can also be precipitated from a solution of the free base inan organic solvent by adding to the solution an appropriate mineral ororganic acid.

Those compounds of formulas 1 and 2 that are acidic in nature, arecapable of forming base salts with various pharmacologically acceptablecations. Examples of such salts include the alkali metal oralkaline-earth metal salts and particularly, the sodium and potassiumsalts. These salts are all prepared by conventional techniques. Thechemical bases which are used as reagents to prepare thepharmaceutically acceptable base salts of this invention are those whichform non-toxic base salts with the acidic compounds of formulas 1 and 2.Such non-toxic base salts include those derived from suchpharmacologically acceptable cations as sodium, potassium calcium andmagnesium, etc. These salts can easily be prepared by treating thecorresponding acidic compounds with an aqueous solution containing thedesired pharmacologically acceptable cations, and then evaporating theresulting solution to dryness, preferably under reduced pressure.Alternatively, they may also be prepared by mixing lower alkanolicsolutions of the acidic compounds and the desired alkali metal alkoxidetogether, and then evaporating the resulting solution to dryness in thesame manner as before. In either case, stoichiometric quantities ofreagents are preferably employed in order to ensure completeness ofreaction and maximum yields of the desired final product.

The compounds of the present invention are potent inhibitors of the erbBfamily of oncogenic and protooncogenic protein tyrosine kinases such asepidermal growth factor receptor (EGFR), erbB2, HER3, or HER4 and thusare all adapted to therapeutic use as anti-proliferative agents (e.g.,anticancer) in mammals, particularly in humans. The compounds of thepresent invention are also inhibitors of angiogenesis and/orvasculogenesis. In particular, the compounds of the present inventionare useful in the prevention and treatment of a variety of humanhyperproliferative disorders such as malignant and benign tumors of theliver, kidney, bladder, breast, gastric, ovarian, colorectal, prostate,pancreatic, lung, vulval, thyroid, hepatic carcinomas, sarcomas,glioblastomas, head and neck, and other hyperplastic conditions such asbenign hyperplasia of the skin (e.g., psoriasis) and benign hyperplasiaof the prostate (e.g., BPH). It is, in addition, expected that acompound of the present invention may possess activity against a rangeof leukemias and lymphoid malignancies.

The compounds of the present invention may also be useful in thetreatment of additional disorders in which aberrant expressionligand/receptor interactions or activation or signalling events relatedto various protein tyrosine kinases, are involved. Such disorders mayinclude those of neuronal, glial, astrocytal, hypothalamic, and otherglandular, macrophagal, epithelial, stromal, and blastocoelic nature inwhich aberrant function, expression, activation or signalling of theerbB tyrosine kinases are involved. In addition, the compounds of thepresent invention may have therapeutic utility in inflammatory,angiogenic and immunologic disorders involving both identified and asyet unidentified tyrosine kinases that are inhibited by the compounds ofthe present invention.

The in vitro activity of the compounds of formulas 1 and 2 in inhibitingthe receptor tyrosine kinase (and thus subsequent proliferativeresponse, e.g., cancer) may be determined by the following procedure.

The activity of the compounds of formulas 1 and 2, in vitro, can bedetermined by the amount of inhibition of the phosphorylation of anexogenous substrate (e.g., Lys₃-Gastrin or polyGluTyr (4:1) randomcopolymer (I. Posner et al., J. Biol. Chem. 267 (29), 20638–47 (1992))on tyrosine by epidermal growth factor receptor kinase by a testcompound relative to a control. Affinity purified, soluble human EGFreceptor (96 ng) is obtained according to the procedure in G. N. Gill,W. Weber, Methods in Enzymology 146, 82–88 (1987) from A431 cells(American Type Culture Collection, Rockville, Md.) and preincubated in amicrofuge tube with EGF (2 μg/ml) in phosphorylation buffer+vanadate(PBV: 50 mM HEPES, pH 7.4; 125 mM NaCl; 24 mM MgCl₂; 100 μM sodiumorthovanadate), in a total volume of 10 μl, for 20–30 minutes at roomtemperature. The test compound, dissolved in dimethylsulfoxide (DMSO),is diluted in PBV, and 10 μl is mixed with the EGF receptor /EGF mix,and incubated for 10–30 minutes at 30° C. The phosphorylation reactionis initiated by addition of 20 μl ³³P-ATP/substrate mix (120 μMLys₃-Gastrin (sequence in single letter code for amino acids,KKKGPWLEEEEEAYGWLDF), 50 mM Hepes pH 7.4, 40 μM ATP, 2 μCi γ-[³³P]-ATP)to the EGFr/EGF mix and incubated for 20 minutes at room temperature.The reaction is stopped by addition of 10 μl stop solution (0.5 M EDTA,pH 8; 2 mM ATP) and 6 μl 2N HCl. The tubes are centrifuged at 14,000RPM, 4° C., for 10 minutes. 35 μl of supernatant from each tube ispipetted onto a 2.5 cm circle of Whatman P81 paper, bulk washed fourtimes in 5% acetic acid, 1 liter per wash, and then air dried. Thisresults in the binding of substrate to the paper with loss of free ATPon washing. The [³³P] incorporated is measured by liquid scintillationcounting. Incorporation in the absence of substrate (e.g., lys₃-gastrin)is subtracted from all values as a background and percent inhibition iscalculated relative to controls without test compound present. Suchassays, carried out with a range of doses of test compounds, allow thedetermination of an approximate IC₅₀ value for the in vitro inhibitionof EGFR kinase activity.

The activity of the compounds of formulas 1 and 2, in vivo, can bedetermined by the amount of inhibition of tumor growth by a testcompound relative to a control. The tumor growth inhibitory effects ofvarious compounds are measured according to the methods of Corbett T.H., et al. “Tumor Induction Relationships in Development ofTransplantable Cancers of the Colon in Mice for Chemotherapy Assays,with a Note on Carcinogen Structure”, Cancer Res., 35, 2434–2439 (1975)and Corbett, T. H., et al., “A Mouse Colon-tumor Model for ExperimentalTherapy”, Cancer Chemother. Rep. (Part 2)”, 5 , 169–186 (1975), withslight modifications. Tumors are induced in the left flank by s.c.injection of 1×10⁶ log phase cultured tumor cells (human MDA-MB-468breast or human HN5 head and neck carcinoma cells) suspended in 0.10 mlRPMI 1640. After sufficient time has elapsed for the tumors to becomepalpable (2–3 mm in diameter) the test animals (athymic mice) aretreated with active compound (formulated by dissolution in DMSOtypically at a concentration of 50 to 100 mg/mL followed by 1:9 dilutioninto saline or, alternatively, 1:9 dilution into 0.1% Pluronic™ P105 in0.9% saline) by the intraperitoneal (ip) or oral (po) routes ofadministration twice daily , every 12 hours) for 5 consecutive days. Inorder to determine an anti-tumor effect, the tumor is measured inmillimeters with Vernier calipers across two diameters and the tumorsize (mg) is calculated using the formula: Tumorweight=(length×[width]²)/2, according to the methods of Geran, R. I., etal. “Protocols for Screening Chemical Agents and Natural ProductsAgainst Animal Tumors and Other Biological Systems”, Third Edition,Cancer Chemother. Rep., 3, 1–104 (1972). Results are expressed aspercent inhibition, according to the formula: Inhibition(%)=(TuW_(control)−TuW_(test))/TuW_(control×)100%. The flank site oftumor implantation provides reproducible dose/response effects for avariety of chemotherapeutic agents, and the method of measurement (tumordiameter) is a reliable method for assessing tumor growth rates.

Other methods of assessing the activity of the compounds of the presentinvention are referred to in PCT international application publicationnumber WO 95/21613 (published Aug. 17, 1995) which incorporated hereinby reference.

The in vitro activity of the compounds of formulas 1 and 2 in inhibitingthe KDR/VEGF receptor may be determined by the following procedure.

The ability of the compounds of the present invention to inhibittyrosine kinase activity may be measured using a recombinant enzyme inan assay that measures the ability of compounds to inhibit thephosphorylation of the exogenous substrate, polyGluTyr (PGT, Sigma™,4:1). The kinase domain of the human KDR/VEGF receptor (amino acids805–1350) is expressed in Sf9 insect cells as a glutathioneS-transferase (GST)-fusion protein using the baculovirus expressionsystem. The protein is purified from the lysates of these cells usingglutathione agarose affinity columns. The enzyme assay is performed in96-well plates that are coated with the PGT substrate (0.625 μg PGT perwell). Test compounds are diluted in dimethylsulfoxide (DMSO), and thenadded to the PGT plates so that the final concentration of DMSO in theassay is 1.6% (v/v). The recombinant enzyme is diluted inphosphorylation buffer (50 mM Hepes, pH 7.3, 125 mM NaCl, 24 mM MgCl₂).The reaction is initiated by the addition of ATP to a finalconcentration of 10 μM. After a 30 minute incubation at room temperaturewith shaking, the reaction is aspirated, and the plates are washed withwash buffer (PBS-containing 0.1% Tween-20). The amount of phosphorylatedPGT is quantitated by incubation with a HRP-conjugated (HRP ishorseradish peroxidase) PY-54 antibody (Transduction Labs), developedwith TMB peroxidase (TMB is 3,3′,5,5′-tetramethylbenzidine), and thereaction is quantitated on a BioRad™ Microplate reader at 450 nM.Inhibition of the kinase enzymatic activity by the test compound isdetected as a reduced absorbance, and the concentration of the compoundthat is required to inhibit the signal by 50% is reported as the IC₅₀value for the test compound.

To measure the ability of the compounds to inhibit KDR tyrosine kinaseactivity for the full length protein that exists in a cellular context,the porcine aortic endothelial (PAE) cells transfected with the humanKDR (Waltenberger et al., J. Biol. Chem. 269:26988, 1994) may be used.Cells are plated and allowed to attach to 96-well dishes in the samemedia (Ham's F12) with 10% FBS (fetal bovine serum). The cells are thenwashed, re-fed with serum depleted media that contains 0.1% (v/v) bovineserum albumin (BSA), and allowed to incubate for 24 hours. Immediatelyprior to dosing with compound, the cells are re-fed with the serumdepleted media (without BSA). Test compounds, dissolved in DMSO, arediluted into the media (final DMSO concentration 0.5% (v/v)). At the endof a 2 hour incubation, VEGF₁₆₅ (50 ng/ml final) is added to the mediafor an 8 minute incubation. The cells are washed and lysed in HNTGbuffer (20 mM Hepes, pH 7.5, 150 mM NaCl, 0.2% Triton™ X-100, 10%glycerol, 0.2 mM PMSF (phenymethylsulfonyl fluoride), 1 μg/ml pepstatin,1 μg/ml leupeptin, 1 μg/ml aprotonin, 2 mM sodium pyrophosphate, 2 mMsodium orthovanadate). The extent of phosphorylation of KDR is measuredusing an ELISA assay. The 96-well plates are coated with 1 μg per wellof goat anti-rabbit antibody. Unbound antibody is washed off the plateand remaining sites are blocked with Superblock buffer (Pierce) prior toaddition of the anti-flk-1 C-20 antibody (0.5 μg per plate, Santa Cruz).Any unbound antibody is washed off the plates prior to addition of thecell lysate. After a 2 hour incubation of the lysates with the flk-1antibody, the KDR associated phosphotyrosine is quantitated bydevelopment with the HRP-conjugated PY-54 antibody and TMB, as describedabove. The ability of the compounds to inhibit the VEGF-stimulatedautophosphorylation reaction by 50%, relative to VEGF-stimulatedcontrols is reported as the IC₅₀ value for the test compound.

The ability of the compounds to inhibit mitogenesis in human endothelialcells is measured by their ability to inhibit ³H-thymidine incorporationinto HUVE cells (human umbilical vein endothelial cells, Clonetics™).This assay has been well described in the literature (Waltenberger J etal. J. Biol. Chem. 269: 26988, 1994; Cao Y et al. J. Biol. Chem. 271:3154, 1996). Briefly, 10⁴ cells are plated in collagen-coated 24-wellplates and allowed to attach. Cells are re-fed in serum-free media, and24 hours later are treated with various concentrations of compound(prepared in DMSO, final concentration of DMSO in the assay is 0.2%v/v), and 2–30 μg/ml VEGF,₁₆₅. During the last 3 hours of the 24 hourcompound treatment, the cells are pulsed with ³H thymidine (NEN, 1 μCiper well). The media are then removed, and the cells washed extensivelywith ice-cold Hank's balanced salt solution, and then 2 times with icecold trichloroacetic acid (10% v/v). The cells are lysed by the additionof 0.2 ml of 0.1 N NaOH, and the lysates transferred into scintillationvials. The wells are then washed with 0.2 ml of 0.1 N HCl, and this washis then transferred to the vials. The extent of ³H thymidineincorporation is measured by scintillation counting. The ability of thecompounds to inhibit incorporation by 50%, relative to control (VEGFtreatment with DMSO vehicle only) is reported as the IC₅₀ value for thetest compound.

Administration of the compounds of the present invention (hereinafterthe “active compound(s)”) can be effected by any method that enablesdelivery of the compounds to the site of action. These methods includeoral routes, intraduodenal routes, parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion),topical, and rectal administration.

The amount of the active compound administered will be dependent on thesubject being treated, the severity of the disorder or condition, therate of administration and the judgement of the prescribing physician.However, an effective dosage is in the range of about 0.001 to about 100mg per kg body weight per day, preferably about 1 to about 35 mg/kg/day,in single or divided doses. For a 70 kg human, this would amount toabout 0.05 to about 7 g/day, preferably about 0.2 to about 2.5 g/day. Insome instances, dosage levels below the lower limit of the aforesaidrange may be more than adequate, while in other cases still larger dosesmay be employed without causing any harmful side effect, provided thatsuch larger doses are first divided into several small doses foradministration throughout the day.

The active compound may be applied as a sole therapy or may involve oneor more other anti-tumour substances, for example those selected from,for example, mitotic inhibitors, for example vinblastine; alkylatingagents, for example cis-platin, carboplatin and cyclophosphamide;anti-metabolites, for example 5-fluorouracil, cytosine arabinoside andhydroxyurea, or, for example, one of the preferred anti-metabolitesdisclosed in European Patent Application No. 239362 such asN-(5-[N-(3,4-dihydro-2-methyl-4-oxoquinazolin-6-ylmethyl)-N-methylamino]-2-thenoyl)-L-glutamicacid; growth factor inhibitors; cell cycle inhibitors; intercalatingantibiotics, for example adriamycin and bleomycin; enzymes, for exampleinterferon; and anti-hormones, for example anti-estrogens such asNolvadex™ (tamoxifen) or, for example anti-androgens such as Casodex™(4′-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3′-(trfluoromethyl)propionanilide). Such conjoint treatment may be achieved by way of thesimultaneous, sequential or separate dosing of the individual componentsof the treatment.

The pharmaceutical composition may, for example, be in a form suitablefor oral administration as a tablet, capsule, pill, powder, sustainedrelease formulations, solution, suspension, for parenteral injection asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.The pharmaceutical composition may be in unit dosage forms suitable forsingle administration of precise dosages. The pharmaceutical compositionwill include a conventional pharmaceutical carrier or excipient and acompound according to the invention as an active ingredient. Inaddition, it may include other medicinal or pharmaceutical agents,carriers, adjuvants, etc.

Exemplary parenteral administration forms include solutions orsuspensions of active compounds in sterile aqueous solutions, forexample, aqueous propylene glycol or dextrose solutions. Such dosageforms can be suitably buffered, if desired.

Suitable pharmaceutical carriers include inert diluents or fillers,water and various organic solvents. The pharmaceutical compositions may,if desired, contain additional ingredients such as flavorings, binders,excipients and the like. Thus for oral administration, tabletscontaining various excipients, such as citric acid may be employedtogether with various disintegrants such as starch, alginic acid andcertain complex silicates and with binding agents such as sucrose,gelatin and acacia. Additionally, lubricating agents such as magnesiumstearate, sodium lauryl sulfate and talc are often useful for tabletingpurposes. Solid compositions of a similar type may also be employed insoft and hard filled gelatin capsules. Preferred materials, therefor,include lactose or milk sugar and high molecular weight polyethyleneglycols. When aqueous suspensions or elixirs are desired for oraladministration the active compound therein may be combined with varioussweetening or flavoring agents, coloring matters or dyes and, ifdesired, emulsifying agents or suspending agents, together with diluentssuch as water, ethanol, propylene glycol, glycerin, or combinationsthereof.

Methods of preparing various pharmaceutical compositions with a specificamount of active compound are known, or will be apparent, to thoseskilled in this art. For examples, see Remington's PharmaceuticalSciences, Mack Publishing Company, Easter, Pa., 15th Edition (1975).

The examples and preparations provided below further illustrate andexemplify the compounds of the present invention and methods ofpreparing such compounds. It is to be understood that the scope of thepresent invention is not limited in any way by the scope of thefollowing examples and preparations. As used herein, “h” means hour(s),“min” means minutes, “Et” means ethyl, “THF” means tetrahydrofuran,“DMF” means dimethylformamide, “Ad” means acetyl and “Me” means methyl.

EXAMPLE 1(3R)-(3-Methoxy-pyrrolidin-1-yl)[-7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone

A. 7-Chloro-thieno[3,2-b]pyridine

The title compound was prepared by the method described in patentWO-99/24440, Example 47, the contents of which are hereby incorporatedby reference.

B. Lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxalate

n-Butyllithium (0.13 mol, 52 mL of a 2.5M solution in hexane) was addeddropwise to a solution of 7-chloro-thieno[3,2-b]pyridine (20 g, 0.12mol) in THF (200 mL) at −78° C., and the internal temperature wasmaintained below −70° C. After 1 h the yellow solution was treated withCO₂(g) until a white suspension resulted. The resulting mixture wasallowed to warm to room temperature, then concentrated under reducedpressure to give a white solid. The resulting solid was triturated withether then dried in vacuo to afford the title compound as a white solid(23.5 g, 90%). MS: 213 (MH+); HPLC Rf: 2.50 min.; HPLC purity. 94%.

C.(3R)-(3-hydroxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone

A solution of lithium 7-chloro-thieno[3,2-b]pyridine-2-carboxylate (15.0g, 70.8 mmol), thionyl chloride (53.1 mL, 106.2 mmol), CH₂Cl₂ (600 ml),and DMF (6 ml) was heated to reflux. After 3 h the resulting yellowsolution was concentrated under reduced pressure, and the residue wassuspended in CH₂Cl₂ (500 mL). (3R)-pyrrolidin-3-ol (2.3 g, 26.2 mmol)was then added dropwise. After 12 h the reaction was quenched with 1NNaOH (500 mL), the layers were separated, and the aqueous layer wasextracted with 2×500 mL CH₂Cl₂. The combined organic layers were driedover Na₂SO₄, filtered, then concentrated under reduced pressure. Theresulting solid was triturated with Et₂O then collected by filtration togive a white solid (13.2 g, 70%). MS: 283.2/285.2 (MH+); HPLC Rf: 3.49min.; HPLC purity: 99%.

D.(3R)-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-(3-methoxy-pyrrolidin-1-yl)-methanone

NaH (2.1 g, 53.1 mmol) was added to a solution of(3R)-(3-hydroxy-pyrrolidin-1-yl)-[7-chloro-thieno[3,2-b]pyridin-2-yl]-methanone(5.0 g, 17.7 mmol) in THF (100 mL), at 0° C. The reaction mixture wasallowed to stir for 20 min., and MeI (3.26 g, 22.9 mmol) was addeddropwise. After 3 h the reaction was treated with saturated aqueous KCN.The aqueous layer was extracted with CH₂Cl₂. The combined organic layerswere dried (Na₂SO₄), and the solvent was removed under reduced pressure.Purification by flash chromatography on silica gel, eluting withCH₂Cl₂/MeOH (94:6) afforded the title compound as a white solid (3.2 g,61%). MS: 297.2/299.2 (MH+); HPLC Rf: 4.25 min.; HPLC purity: 95%.

E. 2-Methyl-1H-indol-5-ol

To a solution of 5-methoxy-2-methyl-1H-indole (5 g, 31 mmol) inmethylene chloride (100 mL) at −78° C., was slowly added a solution ofBBr₃ in CH₂Cl₂ (1.0 M, 93 mL, 93 mmol). The reaction mixture was stirredat −78° C. for 4 hours and slowly warmed to room temperature. Thereaction mixture was stirred at room temperature overnight, and cooledto 0° C. The reaction was quenched carefully with water at 0° C. Theaqueous layer was made basic by adding saturated sodium bicarbonatesolution, and then extracted with methylene chloride (3×50 mL). Thecombined organic layers were dried over sodium sulfate and concentratedunder reduced pressure. The crude product was purified by flashchromatography on silica gel eluting with EtOAc/Hexanes (25:75) toafford the title compound as a yellow solid (3.0 g, 60%).

F.(3R)-(3-Methoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone

Cs₂CO₃ (0.495 g, 1.52 mmol) was added to a solution of(3R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3-methoxy-pyrrolidin-1-yl)-methanone(0.228 g, 0.76 mmol) and 2-methyl-1H-indol-5-ol (0.223 9, 1.52 mmol) inDMF (5 mL), and the resulting solution was heated to 90° C. After 20 hthe reaction was quenched with water, EtOAc was added, and the layerswere separated. The aqueous layer was extracted with EtOAc, and thecombined organic layers were dried over Na₂SO₄ then concentrated. Theresulting material was purified on silica gel by flash columnchromatography, eluting with CH₂Cl₂/MeOH (98/2) to afford the titlecompound as a white solid (0.26 g, 84%). MS: 408.8 (MH+); HPLC Rf: 5.394min.; HPLC purity: 97%.

EXAMPLE 2(3S)-(3-Methoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone

The title compound was prepared from (3S)-pyrrolidin-3-ol as startingmaterial, by a procedure analogous to Example 1. MS: 408.5 (MH+); HPLCRf: 5.41 min.; HPLC purity: 98%.

EXAMPLE 3(3R,4R)-(3,4-Dimethoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone

A.(3R,4R)-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-(3,4-dihydroxy-pyrrolidin-1-yl)-methanone

The title compound was prepared from lithium7-chloro-thieno[3,2-b]pyridine-2-carboxylate and(3R,4R)-pyrrolidine-3,4-diol by a procedure analogous to Example 1C. MS:299.3/301.3 (MH+); HPLC Rf: 3.091 min.; HPLC purity: 99%.

B.(3R,4R)-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-(3,4-dimethoxy-pyrrolidin-1-yl)-methanone

NaH (169 mg, 4.23 mmol) was added to a solution of(3R,4R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3,4-dihydroxy-pyrrolidin-1-yl)-methanone(421 mg, 1.41 mmol) in DMF at 0° C. After 1 h, MeI (500 mg, 3.52 mmol)was added dropwise. The resulting solution was allowed to warm to roomtemperature and stir for 1.5 h. The reaction mixture was treated withsaturated KCN (aq) and saturated ammonium chloride (aq). The aqueouslayer was extracted with EtOAc (2×), and the combined organic layerswere dried over magnesium sulfate. The resulting material was purifiedon silica gel by flash column chromatography eluting with CH₂Cl₂/MeOH(98/2) to afford the title compound as a white solid (324 mg, 70%). MS:327.2/329.2 (MH+); HPLC Rf: 4.448 min.; HPLC purity: 99%.

C.(3R,4R)-(3,4-Dimethoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone

The title compound was prepared from(3R,4R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(3,4-dimethoxy-pyrrolidin-1-yl)-methanoneand 2-methyl-1H-indol-5-ol by a procedure analogous to Example 1F. MS438.3 (MH+); HPLC Rf: 5.554 min.; HPLC purity: 97%.

EXAMPLE 4meso-(3,4-Dimethoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone

The title compound was prepared from meso-pyrrolidine-3,4-diol asstarting material by a procedure analogous to Example 3. MS: 438.3(MH+); HPLC Rf: 5.194 min.; HPLC purity: 99%.

EXAMPLE 5(3S,4S)-(3,4-Dimethoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone

The title compound was prepared from (3S,4S)-pyrrolidine-3,4-diol asstarting material by a procedure analogous to Example 3. MS: 438.3(MH+); HPLC Rf: 5.534 min.; HPLC purity 96%.

EXAMPLE 6(R)-(2-Hydroxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone

A.(R)-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-(2-hydroxymethyl-pyrrolidin-1-yl)-methanone

The title compound was prepared from (R)-pyrrolidin-2-yl-methanol by aprocedure analogous to Example 1C. MS: 297.1/299.1 (MH+); HPLC Rf: 3.981min.; HPLC purity: 97%.

B.(R)-(2-Hydroxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone

The title compound was prepared from(R)-(7-chloro-thieno[3,2-b]pyridin-2-yl)-(2-hydroxymethyl-pyrrolidin-1-yl)-methanoneand 2-methyl-1H-indol-5-ol by a procedure analogous to Example 1F. MS:408.3 (MH+); HPLC Rf: 5.146 min.; HPLC purity: 98%.

EXAMPLE 7(S)-(2-Hydroxymethyl-pyrrolidin-1-yl)[-7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone

The title compound was prepared from (S)-pyrrolidin-2-yl-methanol asstarting material by a procedure analogous to Example 6. MS: 408.2(MH+); HPLC purity: 5.153 min.; HPLC purity: 94%.

EXAMPLE 8(2R)-(2-Methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone

A.(2R)-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-(2-methoxymethyl-pyrrolidin-1-yl)-methanone

The title compound was prepared from lithium7-chloro-thieno[3,2-b]pyridine-2-carboxylate and2-methoxymethyl-pyrrolidine by a procedure analogous to Example 1C. MS:312/314 (MH+); HPLC Rf: 4.87 min; HPLC purity: 99%.

B.(2R)-(2-Methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone

The title compound was prepared from(7-chloro-thieno[3,2-b]pyridin-2-yl)-(2-hydroxymethyl-pyrrolidin-1-yl)-methanoneand 2-methyl-1H-indol-5-ol by a procedure analogous to Example 1F. MS:422 (MH+); HPLC Rf: 5.89 min; HPLC purity: 99%.

EXAMPLE 9(2S)-(2-Methoxymethyl-pyrrolidin-1-yl)[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone

The title compound was prepared by the method described for Example 8,using (2S)-2-methoxymethyl-pyrrolidine as the starting material. MS: 422(MH+); HPLC Rf: 5.90 min; HPLC purity: 98%.

EXAMPLE 10(R)-[7-(1-Ethyl-2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-(2-methoxymethyl-pyrrolidin-1-yl)-methanone

NaH (16 mg, 0.4 mmol) was added to a solution of(2R)-(2-methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone(85 mg, 0.2 mmol) in DMF (5 mL), at 0° C. The reaction mixture wasallowed to stir for 20 min, and EtI (57 mg, 0.40 mmol) was addeddropwise. After 3 h the reaction was quenched with saturated aqueous KCN(10 mL). The aqueous layer was extracted with CH₂Cl₂ (3×15 mL). Thecombined organic extracts were dried (Na₂SO₄), and the solvent wasremoved. Purification by flash chromatography on silica gel (CH₂Cl₂/MeOH94:6) afforded the title compound as a white solid (46 mg, 51%). MS: 450(MH+); HPLC Rf: 6.83 min; HPLC purity: 95%.

EXAMPLE 11(2R)-[7-(1,2-Dimethyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-(2-methoxymethyl-pyrrolidin-1-yl)-methanone

The title compound was prepared by the method described for Example 10,using(2R)-(2-methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanoneand methyl iodide. MS: 436 (MH+); HPLC Rf: 6.33 min; HPLC purity: 96%.

EXAMPLE 12(2R)-1-{5-[2-(2-Methoxymethyl-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxyl]-2-methyl-indol-1-yl-ethanone

To a solution of(2R)-(2-methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanoneand DMAP (120 mg, 0.28 mmol) in DMF (5 mL) was added acetyl chloride (44mg, 0.56 mmol). After 3 h the reaction was quenched with water (5 mL).The aqueous layer was extracted with CH₂Cl₂ (2×15 mL). The combinedorganic extracts were dried (Na₂SO₄), and concentrated onto silica gel(5 mL). Purification by flash chromatography on silica gel (CH₂Cl₂/MeOH97:3) afforded the title compound as a white solid (0.36 g, 69%). MS:464 (MH+); HPLC Rf: 6.12 min; HPLC purity: 96%.

EXAMPLE 13(2R)-R[7-(1-Methanesulfonyl-2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-(2-methoxymethyl-pyrrolidin-1-l)-methanone

The title compound was prepared by the method described for Example 12from(2R)-(2-methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanoneand methanesulfonyl chloride. MS: 501 (MH+); HPLC Rf: 6.13 min; HPLCpurity: 97%.

EXAMPLE 142-(3-Methyl-3H-imidazol-4-yl)-7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine

A. 7-Chloro-2-(3-methyl-3H-imidazol-4-yl)-thieno[3,2-b]pyridine

The title compound was prepared by the method described in PCTapplication WO-99/24440. Example 148. MS: 361 (MH+); HPLC Rf: 5.37 min;HPLC purity: 98%.

B.2-(3-Methyl-3H-imidazol-4-yl)-7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine

The title compound was prepared by the method described for Example 1F.MS: 361 (MH+); HPLC Rf: 5.94 min; HPLC purity: 99%.

EXAMPLE 152-(1-Methyl-1H-imidazol-2-yl)-7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine

A. 7-Chloro-2-(1-methyl-1H-imidazol-2-yl)-thieno[3,2-b]pyridine

The title compound was prepared by the method described in PCTapplication WO-99/24440, Example 149. MS: 251 (MH+); HPLC Rf: 5.02 min;HPLC purity: 95%.

B.2-(1-Methyl-1H-imidazol-2-yl)-7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine

The title compound was prepared by the method described for Example 1F.MS: 361 (MH+); HPLC RM: 5.61 min; HPLC purity: 97%.

EXAMPLE 162-{2-[7-(2-Methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-4-yl}-propan-2-ol

A. 7-Chloro-thieno[3,2-b]pyridine-2-carbothioic acid methoxymethyl amide

Solid 7-chloro-thieno[3,2-b]pyridine (60 g, 360 mmol) was added withstirring to 600 mL dry THF. Nitrogen was bubbled through the solutionfor ten minutes then cooled to −78° C. n-Butyl lithium (170 mL, 432mmol) (2.5 M solution in hexanes) was added drop-wise at a rate suchthat the temperature is maintained below −65° C. The reaction mixturewas stirred at −78° C. for three hours. Methoxymethyl isothiocyanate(43.2 mL, 468 mmol) in 400 mL THF was slowly added. Complete solutionwas noted after the addition was complete. The reaction mixture was thenallowed to stir at −78° C. for three hours. The reaction mixture wasremoved from the cooling bath and 150 mL saturated NH₄Cl solution wasadded. The reaction mixture turned a bright yellow color. THF wasremoved under reduced pressure, and7-Chloro-thieno[3,2-b]pyridine-2-carbothioic acid methoxymethyl amidewas filtered, washed with ethyl acetate and dried giving 93.7 g, a 95%yield as a yellow-orange solid. C₁₀H₉ClN₂OS₂: APCI m/z 273.0/274.9(MH+).); ¹H NMR (d₆-DMSO): δ 8.60 (d, 1H, J=5.0 Hz ), 8.13 (s, 1H), 7.55(d, 1H, J=5.0 Hz ), 4.97 (s, 2H), 2.46 (s, 3H) ppm.

B. 7-chloro-thieno[3,2-b]pyridine-2-carbothioic acid amide

To a solution of 7-Chloro-thieno[3,2-b]pyridine-2-carbothioic acidmethoxymethyl-amide (93.9 g, 344 mmol) and 900 mL THF was added 1 N HCl(344 mL, 344 mmol). The reaction mixture was heated to reflux forseventy-two hours. The reaction mixture was cooled to 0° C., and 300 mLof concentrated NH₄OH was added and stirred. The THF was removed underreduced pressure and the residue was suspended in ethyl acetate andstirred. The precipitate was filtered, washed with ethyl acetate anddried to give 7-chloro-thieno[3,2-b]pyridine-2-carbothioic acid amide(66.7 g) in 85% yield. C₈H₅ClN₂S₂: APCI m/z: 228.9/230.9 (MH+); ¹H NMR(d₆-DMSO): δ 10.24 (s, 1H), 9.94 (s, 1H), 8.65 (d, 1H, J=5.0 Hz), 8.19(s, 1H), 7.62 (d, 1H, J=5.0 Hz) ppm.

C. 2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-thiazole-4-carboxylic acidethyl ester

To a solution of 7-Chloro-thieno[3,2-b]pyridine-2-carbothioic acid amide(5.00 g, 21.9 mmol) in 60 mL of THF was added ethyl bromopyruvate (4.11mL, 32.8 mmol). The reaction mixture was stirred at room temperatureunder nitrogen overnight. The reaction mixture was cooled to 0° C., and30 mL trifluoroacetic anhydride was added. The reaction was stirred atroom temperature for four hours then cooled to 0° C. The reaction wastreated with 30 mL of concentrated NH₄OH followed by removal of THFunder reduced pressure. The dark, oily residue was partitioned betweenwater and ethyl acetate. The aqueous layer was separated and washed withethyl acetate. The combined organic layers were washed with brine, driedover magnesium sulfate, and evaporated under reduced pressure to give abrown oily residue. Chromotography (99.5:0.45:0.05 CHCl₃:CH₃OH:NH₄OH)over silica gel gave a 67% of2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-thiazole-4-carboxylic acid ethylester (3.42 g) as a pale yellow solid. C₁₃H₉ClN₂O₂S₂: APCI m/z325.0/327.0 (MH+); 232.9/325.9 (neg.); ¹H NMR (d₆-DMSO): δ 8.67 (d, 1H,J=5.0 Hz), 8.37 (s, 1H), 7.62 (d, 1H, J=5.0 Hz), 3.98 (q, 2H, J=7.0 Hz),1.13 (t, 3H, J=7.0 Hz) ppm.

D. 2-[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-thiazol-4-yl]-propan-2-ol

To a solution of2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-thiazole-4-carboxylic acid ethylester (220 mg, 0.677 mmol) in 3.0 mL dry THF cooled to −78° C. was addedmethyl magnesium bromide (3.0 M in THF) (564 μL, 1.69 mmol). Thereaction was stirred at −78° C. for four hours, removed from the coolingbath and quenched with 1 mL of saturated NH₄Cl solution. The reactionwas extracted with ethyl acetate and saturated NaHCO₃. The aqueous layerwas washed with ethyl acetate. The combined organic layers were washedwith brine, dried over magnesium sulfate, and evaporated under reducedpressure giving a brown solid. Silica gel chromatography (98:1.8:0.2CHCl₃:CH₃OH:NH₄OH) of the residue gave a 48% yield of2-[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-thiazol-4-yl]-propan-2-ol (0.1g) as a yellow solid. C₁₃H₁₁ClN₂OS₂ C₁₃H₁₁ClN₂OS₂: APCI m/z 311.1/313.1(MH+); ¹H NMR (d₆-DMSO) δ 8.67 (d, 1H, J=5.4 Hz), 8.20 (s, 1H), 7.61 (d,1H, J=5.4 Hz), 7.60 (s, 1H), 1.48 (s, 6H) ppm.

E. 2-methyl-1H-indol-5-ol

A solution of 5-Methoxy-2-methyl-1H-indole (2 g, 12.4 mmol) in 10 mLdichloromethane was cooled to −78° C. A 1.0 M solution of BBr₃ indichloromethane (30 mL, 30.0 mmol) was added and the resultant mixturewas stirred at −78° C. for three hours. The reaction was carefullyquenched into ice water and extracted with dichloromethane two times.The combined organic layers were washed with brine, dried over magnesiumsulfate, and evaporated under reduced pressure to give a dark oil.Silica gel chromatography (98:1.8:0.2 CHCl₃:CH₃OH:NH₄OH) of the residuegave a 60% yield of 2-methyl-1H-indol-5-ol (1.09 g) as a tan solid.C₉H₉NO: GC/MS: r.t.=2.88 min., m/z 146. ¹H NMR (CD₃OD): δ 7.03 (d, 1H,J=8.7 Hz), 6.77 (s, 1H), 6.53 (D, 1H, J=8.7 Hz), 5.92 (s, 1H), 2.32 (s,3H) ppm.

F.2-{2-[7-(2-Methyl-1H-indol-5-yloxy-thieno[3,2-b]pyridin-2-yl]-thiazol-4-yl}-propan-2-ol

A solution of2-[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-thiazol-4-yl]-propan-2-ol (100mg, 0.322 mmol), DMF 0.7 mL, cesium carbonate (210 mg, 0.644 mmol) and2-methyl-1H-indol-5-ol and (95.0 mg, 0.644 mmol) was heated to 85° C.for sixteen hours. The reaction mixture was cooled to room temperatureand extracted with 5% methanol/ethyl acetate and water. The layers wereseparated, and the aqueous layer was washed with a 5% methanol and ethylacetate solution. The combined organic layers were washed with brine,dried over magnesium sulfate, and evaporated under reduced pressure togive an oily brown solid. Silica gel chromatography (98:1.8:0.2CHCl₃:CH₃OH:NH₄OH) afforded the titled compound (46 mg) as an off-whitesolid in 17% yield. C₂₂H₁₉N₃O₂S₂: APCI m/z 422.2 (pos.); ¹H NMR (CD₃OD):δ 8.38 (d, 1H, J=5.6 Hz), 7.89 (s, 1H), 7.47 (s, 1H), 7.35 (d, 1H, J=8.7Hz), 7.26 (s, 1H), 6.87 (d, 1H, J=8.7 Hz), 6.57 (d, 1H, J=5.6 Hz), 6.17(s, 1H), 2.43 (s, 3H), 1.61 (s, 6H) ppm.

EXAMPLE 172-{2-[7-(2-Methyl-quinolin-6-)yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-4-yl}-propan-2-ol

The title compound (23 mg, 16%) was prepared from2-[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-thiazol-4-yl]-propan-2-ol and2-methylquinolin-6-ol by a procedure analogous to Example 16.C₂₃H₁₉N₃O₂S₂: APCI m/z 434.2 (pos.); HPLC r.t.=6.406 min.; ¹H NMR(CD₃OD): δ 8.48 (d, 1H, J=5.4 Hz), 8.24 (d, 1H, J=8.4 Hz), 8.08 (d, 1H,J=9.1 Hz), 7.92 (s, 1H), 7.77 (s, 1H), 7.66 (d, 1H, J=9.1 Hz), 7.48 (d,1H, J=8.4 Hz), 7.48 (s, 1H), 6.76 (d, 1H, J=5.4 Hz), 2.73 (s, 3H), 1.60(s, 6H) ppm.

EXAMPLE 182-{2-[7-(Quinolin-6-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-4-}-propan-2-ol

The title compound (9 mg, 7%) was prepared from2-[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-thiazol-4-yl]-propan-2-ol andquinolin-6-ol by a procedure analogous to Example 16. C₂₂H₁₇N₃O₂S₂: APCIm/z 420.2 (MH+); ¹H NMR (CD₃OD): δ 8.87 (d, 1H, J=4.3 Hz), 8.48 (d, 1H,J=5.4 Hz), 7.91 (s, 1H), 7.81 (s, 1H), 7.70 (d, 1H, J=9.1 Hz), 7.57 (dd,1H, J=9.1, 4.3 Hz), 7.47 (s, 1H), 6.77 (d, 1H, J=5.4 Hz), 1.59 (s, 6H)ppm.

EXAMPLE 192-{2-[7-(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-4-yl}-propan-2-ol

The title compound (11 mg, 8%) was prepared from2-[2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-thiazol-4-yl]-propan-2-ol and1-methyl-5-trifluoromethyl-1H-pyrazol-3-ol by a procedure analogous toExample 16. C₁₈H₁₅F₃N₄O₂S₂: APCI m/z 441.3 (pos.); ¹H NMR (CD₃OD): δ8.53 (d, 1H, J=5.6 Hz), 7.91 (s, 1H), 7.48 (s, 1H), 7.07 (d, 1H, J=5.6Hz), 6.68 (s, 1H), 3.98 (s, 3H), 1.61 (s, 6H) ppm.

EXAMPLE 20{4-Methyl-2-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-(4-methyl-piperazin-1-yl)-methanone

A. 2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carboxylicacid ethyl ester

19.5 g (85.6 mmol) of 7-chloro-thieno[3,2-b]pyridine-2-carbothioic acidamide was added to 160 mL of a 1:1 DMF:THF solution mixture and cooledto 0° C. To this solution was slowly added 17.7 mL (128 mmol) of ethyl2-chloroacetoacetate. After addition, the reaction was heated to 80° C.for sixteen hours. The reaction was cooled to room temperature andextracted with dichloromethane and water. The organic layer wasseparated and dried over magnesium sulfate, filtered, concentrated andpurified by silica gel chromatography to afford2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carboxylicacid ethyl ester (15.6 g) in 54% yield. C₁₄H₁₁ClN₂O₂S₂: APCI m/z339.1/341.0 (pos.); ¹H NMR (CDCl₃): δ 8.68 (d, 1H , J=5.4 Hz), 8.24 (s,1H), 7.51 (d, 1H, J=5.4 Hz), 4.36 (q, 2H, J=7.1 Hz), 2.77 (s, 3H), 1.38(t, 3H, J=7.1 Hz) ppm.

B. 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carboxylicacid

To a solution of 15.2 g (46.2 mmol)2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carboxylicacid ethyl ester, 80 mL of THF and 20 mL of absolute ethanol was added(13 g, 231 mmol) freshly ground potassium hydroxide. The reaction wasstirred at room temperature for sixteen hours. The reaction was cooledto 0° C. and the pH was adjusted to pH 3 with conc HCl. The resultingyellow precipitate was filtered and dried to give2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carboxylicacid (10.3 g) in 72% yield. C₁₂H₇N₂O₂S₂: APCI m/z 310.2/312.2 (pos.); ¹HNMR (d₆-DMSO): δ 8.67 (d, 1H, J=5.0 Hz), 8.42 (s, 1H), 7.65 (d, 1H,J=5.0 Hz), 2.65 (s, 3H) ppm.

C. 2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carbonylChloride

To a solution of 4 g (12.9 mmol) of2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carboxylicacid 40 mL of 1,2-dichloroethane and 0.1 mL dimethyl formamide wascarefully added 4.7 mL (64.4 mmol) of thionyl chloride. The reaction washeated to 90° C. for five hours. The reaction was cooled to roomtemperature and dry ethyl ether was added. The resulting brownprecipitate was collected by vacuum filtration, washed with diethylether and dried to afford2-(7-chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carbonylchloride (3.31 g) in 78% yield. C₁₂H₆Cl₂N₂OS₂: APCI m/z (in methanol togive methyl ester) 325.1/327.1 (pos.); ¹H NMR (d₆-DMSO): δ 8.68 (d, 1H,J=5.0 Hz), 8.32 (s, 1H), 8.65 (d, 1H, J=5.0 Hz), 2.39 (s, 3H) ppm.

D.[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-(4-methyl-piperazin-1-yl)-methanone

A solution of2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carbonylchloride, (0.28 g, 0.85 mmol), dry dichloromethane (1.5 mL), and1-methylpiperazine (0.21 mL, 1.87 mmol) was stirred at room temperaturefor four hours. A gas discharge and immediate solution were noted. Thereaction mixture was evaporated directly onto silica gel and purifiedthrough silica gel chromatography to afford[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-(4-methyl-piperazin-1-yl)-methanone(0.234 g) in 70% yield. C₁₇H₁₇ClN₄OS₂: APCI 393.2/395.2 (pos.); ¹H NMR(d₆-DMSO): δ 8.68 (d, 1H, J=5.4 Hz), 8.32 (s, 1H), 7.64 (d, 1H, J=5.4Hz), 3.6–3.4 (bm, 4H), 2.38 (s, 3H), 2.4–2.2 (bm, 4H), 2.17 (s, 3H) ppm.

E.{4-Methyl-2-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-(4-methyl-piperazin-1-yl)-methanone

The title compound (77 mg, 51%) was prepared from[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-(4-methyl-piperazin-1-yl)-methanoneand 2-methyl-1H-indol-5-ol by a procedure analogous to Example 16 as atan colored hydrochloride salt. C₂₆H₂₅N₅O₂S₂: APCI m/z 504.3 (pos.); ¹HNMR (CD₃OD): δ 8.46 (d, 1H, J=5.4 Hz), 7.99 (s, 1H), 7.35 (d, 1H, J=8.3Hz), 7.26 (s, 1H), 6.87 (d, 1H, J=8.3 Hz), 6.67 (d, 1H, J=5.4 Hz), 6.17(s, 1H), 3.8–3.0 (bm, 8H), 2.95 (s, 3H), 2.49 (s, 3H), 2.43 (s, 3H) ppm.

EXAMPLE 21 2-Methyl-5-{2-[4-methyl-5-(4-methyl-piperazine-1-carbonyl)-thiazol-2-yl]-thieno[3,2-b]pyridin-7-yloxy}-1H-indole-3-carbonitrile

A. 5-methoxy-2-methyl-1H-indole-3-carbonitrile

To a 0° C. solution of 5-Methoxy-2-methyl-1H-indole (5 g, 31.0 mmol),dry acetonitrile, (90 mL) was slowly added chlorosulfonyl isocyanate (3mL, 34.1 mmol). The reaction was stirred and allowed to warm to roomtemperature and stirred for an additional four hours followed by theaddition of dimethyl formamide (4.8 mL (62.0 mmol)and then stirred foran additional 1.5 hours at room temperature. The reaction was pouredinto water and extracted with diethyl ether. The aqueous layer wasadjusted to pH 9 with 1M potassium carbonate, and extracted with diethylether. The ether layers were combined and dried over magnesium sulfate,filtered and concentrated. Crystallization of the residue from ether andhexane gave 5-methoxy-2-methyl-1H-indole-3-carbonitrile (3.86 g) in 67%yield as a light pink solid. C₁₁H₁₀N₂O: GC/MS r.t.=4.06 min., m/z 186;¹H NMR (CDCl₃): δ 7.22 (d, 1H, J=8.3 Hz), 7.08 (s, 1H), 6.86 (d, 1H,J=8.3 Hz), 3.86 (s, 3H), 2.60 (s, 3H) ppm.

B. 5-methoxy-2-methyl-1H-indole-3-carbonitrile

5-Hydroxy-2-methyl-1H-indole-3-carbonitrile (1.69 g, 61%) was preparedas a white solid after chromatography from5-methoxy-2-methyl-1H-indole-3-carbonitrile by a procedure analogous toExample 16E. C₁₀H₈N₂O: GC/MS, m/z 172; ¹H NMR (DMSO): δ 11.8 (s, 1H),9.1 (s, 1H), 7.20 (d, 1H, J=8.8 Hz), 6.78 (s, 1H), 6.67 (d, 1H, J=8.8Hz), 2.46 (s, 3H) ppm.

C.2-Methyl-5-{2-[4-methyl-5-(4-methyl-piperazine-1-carbonyl)-thiazol-2-yl]-thieno[3,2-b]pyridin-7-yloxy}-1H-indole-3-carbonitrile

The title compound (61 mg, 41%) was prepared from[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-(4-methyl-piperazin-1-yl)-methanoneand 5-Hydroxy-2-methyl-1 H-indole-3-carbonitrile by a procedureanalogous to Example 16 using and in a 41% yield. C₂₇H₂₅N₆O₂S₂: APCI m/z529.4 (pos.); ¹H NMR (CD₃OD): δ 8.72 (d, 1H, J=6.6 Hz), 8.17 (s, 1H),7.60 (d, 1H, J=8.7 Hz), 7.58 (s, 1H), 7.23 (d, 1H, J=8.7 Hz), 7.07 (d,1H, J=6.6 Hz), 3.65–3.15 (bm, 8H), 2.96 (s, 3H), 2.63 (s, 3H), 2.52 (s,3H) ppm.

EXAMPLE 22{4-Methyl-2-[7-(5-phenyl-1H-pyrazol-3-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-morpholin-4-yl-methanone

A. 5-Phenyl-1,2-dihydro-pyrazol-3-one

A vigorously stirred solution of ethyl benzoylacetate (30 g 150 mmol),of 5% aqueous sodium hydroxide (312 mL), and hydrazine hydrate (14.6 mL468 mmol) was heated to 75° C. for sixteen hours. The resultantprecipitate was filtered, washed with water and dried and gave5-Phenyl-1,2-dihydro-pyrazol-3-one (20.3) in 81% yield as a white solid.C₉H₈N₂O: ¹H NMR (d₆-DMSO): δ 7.62 (d, 2H, J=7.0 Hz), 7.36 (t, 2H, J=7.0Hz), 7.26 (t, 1H, J=7.0 Hz), 5.85 (s, 1H) ppm.

B.[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-morpholin-4-yl-methanone

[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-morpholin-4-yl-methanone (532 mg, 82%) wasprepared from2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazole-5-carbonylchloride and morpholine in a procedure analogous to Example 20.C₁₆H₁₄ClN₃O₂S₂: APCI m/z 380.0/382.1 (pos.).

C.{4-Methyl-2-[7-(5-phenyl-1H-pyrazol-3-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-morpholin-4-yl-methanone

The title compound (37 mg, 17%) was prepared from[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-morpholin-4-yl-methanoneand 5-Phenyl-1,2-dihydro-pyrazol-3-one by a procedure analogous toExample 16 1. C₂₅H₂₁N₅O₃S₂: APCI m/z 503.5 (pos.); ¹H NMR (CD₃OD): δ8.55 (d, 1H, J=5.8 Hz), 8.00 (s, 1H), 7.72 (d, 2H, J=7.1 Hz), 7.46 (t,2H, J=7.1 Hz), 7.41 (t, 1H, J=7.1 Hz), 7.08 (d, 1H, J=5.8 Hz), 6.53 (s,1H), 3.71–3.60 (bm, 8H), 2.46 (s, 3H) ppm.

EXAMPLE 23(2-{7-[5-(4-Fluoro-phenyl)-1H-pyrazol-3-yloxy]-thieno[3,2-b]pyridin-2-yl}-4-methyl-thiazol-5-yl)-(4-methyl-piperazin-1-yl)-methanone

A. 5-(4-Fluoro-phenyl)-1H-pyrazol-3-ol

5-(4-Fluoro-phenyl)-1H-pyrazol-3-ol (7.67 g, 84%) was prepared as awhite solid from 3-(4-Fluoro-phenyl)-3-oxo-propionic acid methyl ester(10.0 g, 51.0 mmol) and hydrazine (4.76 mL, 153 mmol) by a procedureanalogous to Example 22. C₉H₇FN₂O: ¹H NMR (d₆-DMSO): δ 7.66 (dd, 2H,J_(CH—CF)=11.7 Hz, J_(CH—CH)=8.7 Hz), 7.21 (d, 2H, J=8.7 Hz), 5.83 (s,1H) ppm.

B.(2-{7-[5-(4-Fluoro-phenyl)-1H-pyrazol-3-yloxy]-thieno[3,2-b]pyridin-2-yl}-4-methyl-thiazol-5-yl)-(4-methyl-piperazin-1-yl)-methanone

The title compound (36.4 mg, 17%) was prepared from[2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-morpholin-4-yl-methanoneand 5-(4-Fluoro-phenyl)-1H-pyrazol-3-ol by a procedure analogous toExample 22. C₂₆H₂₃FN₆O₂S₂: APCI m/z 535.0 (MH+); ¹H NMR (CD₃OD): δ 8.84(d, J=6.6 Hz, 1H), 8.20 (s, 1H), 7.78 (dd, J_(CH—CF)=11.8 Hz,J_(CH—CH)=8.8 Hz, 2H), 7.61 (d, J=6.6 Hz, 1H), 7.25 (d, J=8.8 Hz, 2H),6.64 (s, 1H), 3.6–3.1 (bm, 8H), 2.96 (s, 3H), 2.53 (s, 3H) ppm.

EXAMPLE 242-{7-[5-(4-Methoxy-phenyl)-1H-pyrazol-3-yloxy]-thieno[3,2-b]pyridin-2-yl}-4-methyl-thiazol-5-yl)-(4-methyl-piperazin-1-yl)-methanone

A. 5-(4-Methoxy-phenyl)-1H-pyrazol-3-ol

5-(4-Methoxy-phenyl)-1H-pyrazol-3-ol (30.8 g, 99%) was prepared as awhite solid from 3-(4-methoxy-phenyl)-3-oxo-propionic acid ethyl ester(29.9 mL, 156 mmol) and hydrazine hydrate (14.6 mL, 468 mmol) by aprocedure analogous to Example 22. C₁₀H₁₀N₂O₂: ¹H NMR (D₆-DMSO): δ 7.55(d, J=8.8 Hz, 2H), 6.93 (d, J=8.8 Hz, 2H), 5.75 (s, 1H), 3.73 (s, 3H)ppm.

B.2-{7-[5-(4-Methoxy-phenyl)-1H-pyrazol-3-yloxy]-thieno[3,2-b]pyridin-2-yl}-4-methyl-thiazol-5-yl)-(4-methyl-piperazin-1-yl)-methanone

The title compound (8 mg, 4%) was prepared from5-(4-methoxy-phenyl)-1H-pyrazol-3-ol (109 mg, 0.573 mmol) and[2-(7chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-morpholin-4-yl-methanone(150 mg, 0.382 mmol) by a procedure analogous to Example 16.C₂₇H₂₆N₆O₃S₂: APCI m/z 547.0 (MH+); ¹H NMR (CDCl₃): δ 8.52 (d, J=5.4 Hz,1H), 7.85 (s, 1H), 7.48 (d, J=8.7 Hz, 2H), 7.00 (d, J=5.4 Hz, 1H), 6.86(d, J=8.7 Hz, 2H), 6.18 (s, 1H), 3.77 (s, 3H), 3.80–3.55 (bm, 8H), 2.46(s, 3H), 2.32 (s, 3H) ppm.

1. A compound of the formula 1 or 2

or a pharmaceutically acceptable salts or solvates thereof, wherein X isCH; R¹ is H, C₁–C₆ alkyl, —C(O)(C₁–C₆ alkyl), C₆–C₁₀ aryl or 5 to 13membered heterocyclic, wherein said C₆–C₁₀ aryl and 5 to 13 memberedheterocyclic groups are optionally substituted by 1 to 5 R⁵substituents; each R⁵ is independently selected from halo, cyano, nitro,trifluoromethoxy, trifluoromethyl, azido, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸,—OC(O)OR⁸, —NR⁶C(O)R⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —OR⁹, —SO₂NR⁶R⁷, C₁–C₆ alkyl,—(CH₂)_(j)O(CH₂)_(q)NR⁶R⁷, —(CH₂)_(t)O(CH₂)_(q)OR⁹, —(CH₂)_(t)OR⁹,—S(O)_(j)(C₁–C₆ alkyl), —(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to 10membered heterocyclic), —C(O)(CH₂)_(t)(C₆–C₁₀ aryl),—(CH₂)_(t)O(CH₂)_(j)(C₆–C₁₀aryl), —(CH₂)_(t)O(CH₂)_(q)(5 to 10 memberedheterocyclic), —C(O)(CH₂)_(t)(5 to 10 membered heterocyclic),—(CH₂)_(j)NR⁷(CH₂)_(q)NR⁶R⁷, —(CH₂)_(j)NR⁷CH₂C(O)NR⁶R⁷,—(CH₂)_(j)NR⁷(CH₂)_(q)NR⁹C(O)R⁸, —(CH₂)_(j)NR⁷(CH₂)_(t)O(CH₂)_(q)OR⁹,—(CH₂)_(j)NR⁷(CH₂)_(q)S(O)_(j)(C₁–C₆ alkyl), —(CH₂)_(j)NR⁷(CH₂)_(t)R⁶,—SO₂(CH₂)_(t)(C₆–C₁₀ aryl), and —SO₂(CH₂)_(t)(5 to 10 memberedheterocyclic), wherein j is an integer from 0 to 2, t is an integer from0 to 6, q is an integer from 2 to 6, the —(CH₂)_(q)— and —(CH₂)_(t)—moieties of the foregoing R⁵ groups optionally include a carbon-carbondouble or triple bond where t is an integer between 2 and 6, and thealkyl, aryl and heterocyclic moieties of the foregoing R⁵ groups areoptionally substituted by 1 to 3 substituents independently selectedfrom halo, cyano, nitro, trifluoromethyl, azido, —C(O)R⁸, —C(O)OR⁸,—OC(O)R⁸, —OC(O)OR⁸, —NR⁶C(O)R⁷, —C(O)NR⁶R⁷, —(CH₂)_(t)NR⁶R⁷, C₁–C₆alkyl, —(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to 10 memberedheterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹, and —(CH₂)_(t)OR⁹, wherein t isan integer from 0 to 6 and q is an integer from 2 to 6; each R⁶ and R⁷is independently selected from H, C₁–C₆ alkyl, —(CH₂)_(t)(C₆–C₁₀ aryl),—(CH₂)_(t)(5 to 10 membered heterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹, and—(CH₂)_(t)OR⁹, wherein t is an integer from 0 to 6 and q is an integerfrom 2 to 6, and the alkyl, aryl and heterocyclic moieties of theforegoing R⁶ and R⁷ groups are optionally substituted by 1 to 3substituents independently selected from halo, cyano, nitro,trifluoromethyl, azido, —C(O)R⁸, —C(O)OR⁸, —CO(O)R⁸, —OC(O)OR⁸,—NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰, —NR⁹R¹⁰, C₁–C₆ alkyl, —(CH₂)_(t)(C₆–C₁₀ aryl),—(CH₂)_(t)(5 to 10 membered heterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹, and—(CH₂)_(t)OR⁹, wherein t is an integer from 0 to 6 and q is an integerfrom 2 to 6, with the proviso that where R⁶ and R⁷ are both attached tothe same nitrogen, then R⁶ and R⁷ are not both bonded to the nitrogendirectly through an oxygen; each R⁸ is independently selected from H,C₁–C₁₀ alkyl, —(CH₂)_(t)(C₆–C₁₀ aryl), and —(CH₂)_(t)(5 to 10 memberedheterocyclic), wherein t is an integer from 0 to 6; each R⁹ and R¹⁰ isindependently selected from H and C₁–C₆ alkyl; and, R¹¹ is C₁–C₆ alkyl,—C(O)NR¹²R¹³, —C(O)(C₆–C₁₀ aryl), —(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5to 10 membered heterocyclic), —(CH₂)_(t)NR¹²R¹³, —SO₂NR¹²R¹³ and—CO₂R¹², wherein t is an integer from 0 to 6, wherein said R¹¹ groupsC₁–C₆ alkyl, —C(O)(C₆–C₁₀ aryl), —(CH₂)_(t)(C₆–C₁₀ aryl), and—(CH₂)_(t)(5 to 10 membered heterocyclic) are optionally substituted by1 to 5 R⁵ groups, and wherein each R¹² and R¹³ is independently selectedfrom H, C₁–C₆ alkyl, —(CH₂)_(t)(C₃–C₁₀ cycloalkyl), —(CH₂)_(t)(C₆–C₁₀aryl), —(CH₂)_(t)(5 to 10 membered heterocyclic),—(CH₂)_(t)O(CH₂)_(q)OR⁹, and —(CH₂)_(t)OR⁹, q is an integer from 2 to 6,and the alkyl, aryl and heterocyclic moieties of the foregoing R¹² andR¹³ groups are optionally substituted by 1 to 3 substituentsindependently selected from R⁵ or R¹² and R¹³ are taken together withthe nitrogen to which they are attached to form a C₅–C₉ azabicyclic,aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinylring, wherein said C₅–C₉ azabicyclic, aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,isoquinolinyl, or dihydroisoquinolinyl ring are optionally substitutedby 1 to 5 R⁵ substituents, with the proviso R¹² and R¹³ are not bothbonded to the nitrogen directly through an oxygen.
 2. A compound ofclaim 1, wherein R¹¹ is —(CH₂)_(t)(5 to 10 membered heterocyclic),—C(O)NR¹²R¹³, —(CH₂)_(t)NR¹²R¹³, —SO₂NR¹²R¹³ and —CO₂R¹², wherein t isan integer from 0 to 6, wherein said R¹¹ group —(CH₂)_(t)(5 to 10membered heterocyclic) is optionally substituted by 1 to 5 R⁵ groups andwherein each R¹² and R¹³ is independently selected from H, C₁–C₆ alkyl,—(CH₂)_(t)(C₃–C₁₀ cycloalkyl), —(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to10 membered heterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹, —(CH₂)_(t)OR⁹, q isan integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties ofthe foregoing R¹² and R¹³ groups are optionally substituted by 1 to 3substituents independently selected from R⁵ or R¹² and R¹³ are takentogether with the nitrogen to which they are attached to form a C₅–C₉azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, ordihydroisoquinolinyl ring, wherein said C₅–C₉ azabicyclic, aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring areoptionally substituted by 1 to 5 R⁵ substituents, with the proviso R¹²and R¹³ are not both bonded to the nitrogen directly through an oxygen.3. A compound of claim 2, wherein R¹¹ is —(CH₂)_(t)(5 to 10 memberedheterocyclic), —C(O)NR¹²R¹³, —SO₂NR¹²R¹³ and —CO₂R¹², wherein t is aninteger from 0 to 6, wherein said R¹¹ group —(CH₂)_(t)(5 to 10 memberedheterocyclic) is optionally substituted by 1 to 5 R⁵ groups and whereineach R¹² and R¹³ is independently selected from H, C₁–C₆ alkyl,—(CH₂)_(t)(C₃–C₁₀ cycloalkyl), —(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to10 membered heterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹, —(CH₂)_(t)OR⁹, q isan integer from 2 to 6, and the alkyl, aryl and heterocyclic moieties ofthe foregoing R¹² and R¹³ groups are optionally substituted by 1 to 3substituents independently selected from R⁵ or R¹² and R¹³ are takentogether with the nitrogen to which they are attached to form a C₅–C₉azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, ordihydroisoquinolinyl ring, wherein said C₅–C₉ azabicyclic, aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring areoptionally substituted by 1 to 5 R⁵ substituents, with the proviso R¹²and R¹³ are not both bonded to the nitrogen directly through an oxygen.4. A compound of claim 3, wherein R¹¹ is —(CH₂)_(t)(5 to 10 memberedheterocyclic) and —C(O)NR¹²R¹³, wherein t is an integer from 0 to 6,wherein said R¹¹ group —(CH₂)_(t)(5 to 10 membered heterocyclic) isoptionally substituted by 1 to 5 R⁵ groups and wherein each R¹² and R¹³is independently selected from H, C₁–C₆ alkyl, —(CH₂)_(t)(C₃–C₁₀cycloalkyl), —(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to 10 memberedheterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹, —(CH₂)_(t)OR⁹, q is an integerfrom 2 to 6, and the alkyl, aryl and heterocyclic moieties of theforegoing R¹² and R¹³ groups are optionally substituted by 1 to 3substituents independently selected from R⁵ or R¹² and R¹³ are takentogether with the nitrogen to which they are attached to form a C₅–C₉azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, ordihydroisoquinolinyl ring, wherein said C₅–C₉ azabicyclic, aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring areoptionally substituted by 1 to 5 R⁵ substituents, with the proviso R¹²and R¹³ are not both bonded to the nitrogen directly through an oxygen.5. A compound of claim 4, wherein R¹¹ is —C(O)NR¹²R¹³, wherein R¹² andR¹³ are independently selected from H, C₁–C₆ alkyl, —(CH₂)_(t)(C₃–C₁₀cycloalkyl), —(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to 10 memberedheterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹, —(CH₂)_(t)OR⁹, wherein t is aninteger from 0 to 6, q is an integer from 2 to 6, and the alkyl, aryland heterocyclic moieties of the foregoing R¹² and R¹³ groups areoptionally substituted by 1 to 3 substituents independently selectedfrom R⁵ or R¹² and R¹³ are taken together with the nitrogen to whichthey are attached to form a C₅–C₉ azabicyclic, aziridinyl, azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,isoquinolinyl, or dihydroisoquinolinyl ring, wherein said C₅–C₉azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, ordihydroisoquinolinyl ring are optionally substituted by 1 to 5 R⁵substituents, with the proviso R¹² and R¹³ are not both bonded to thenitrogen directly through an oxygen.
 6. A compound of claim 5, whereinR¹¹ is —C(O)NR¹²R¹³, wherein R¹² and R¹³ are taken together with thenitrogen to which they are attached to form a C₅–C₉ azabicyclic,aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinylring, wherein said C₅–C₉ azabicyclic, aziridinyl. azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,isoquinolinyl, or dihydroisoquinolinyl ring are optionally substitutedby 1 to 5 R⁵ substituents.
 7. A compound of claim 6, wherein R¹¹ is—C(O)NR¹²R¹³, wherein R¹² and R¹³ are taken together with the nitrogento which they are attached to form a pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, ordihydroisoquinolinyl ring, wherein said pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, ordihydroisoquinolinyl ring are optionally substituted by 1 to 5 R⁵substituents.
 8. A compound of claim 7, wherein R¹¹ is —C(O)NR¹²R¹³,wherein R¹² and R¹³ are taken together with the nitrogen to which theyare attached to form a pyrrolidinyl, piperidinyl, piperazinyl,morpholinyl, or thiomorpholinyl ring, wherein said pyrrolidinyl,piperidinyl, piperazinyl, morpholinyl, or thiomorpholinyl ring areoptionally substituted by 1 to 5 R⁵ substituents.
 9. A compound of claim8, wherein R¹¹ is —C(O)NR¹²R¹³, wherein R¹² and R¹³ are taken togetherwith the nitrogen to which they are attached to form a pyrrolidinyl orpiperidinyl ring, wherein said pyrrolidinyl or piperidinyl ring areoptionally substituted by 1 to 5 R⁵ substituents.
 10. A compound ofclaim 9, wherein R¹¹ is —C(O)NR¹²R¹³, wherein R¹² and R¹³ are takentogether with the nitrogen to which they are attached to form apyrrolidinyl ring, wherein said pyrrolidinyl is optionally substitutedby 1 to 5 R⁵ substituents.
 11. A compound of claim 10, wherein R¹¹ is—C(O)NR¹²R¹³,wherein R¹² and R¹³ are taken together with the nitrogen towhich they are attached to form a pyrrolidin-1-yl ring, wherein saidpyrrolidin-1-yl is optionally substituted by 1 to 5 R⁵ substituents. 12.A compound of claim 4, wherein R¹¹ is —(CH₂)_(t)(5 to 10 memberedheterocyclic) group, wherein t is an integer from 0 to 6, said—(CH₂)_(t)(5 to 10 membered heterocyclic) group is optionallysubstituted by 1 to 5 R⁵ groups.
 13. A compound of claim 12, wherein R¹¹is —(CH₂)_(t)(5–8 membered heterocyclic) group, wherein t is an integerfrom 0 to 6, said —(CH₂)_(t)(5–8 membered heterocyclic) group isoptionally substituted by 1 to 5 R⁵ groups.
 14. A compound of claim 13,wherein R¹¹ is —(CH₂)_(t)(5 or 6 membered heterocyclic) group, wherein tis an integer from 0 to 6, said —(CH₂)_(t)(5 or 6 membered heterocyclic)group is optionally substituted by 1 to 5 R⁵ groups.
 15. A compound ofclaim 14, wherein R¹¹ is —(CH₂)_(t)(5 membered heterocyclic) group,wherein t is an integer from 0 to 6, said —(CH₂)_(t)(5 memberedheterocyclic) group is optionally substituted by 1 to 5 R⁵ groups.
 16. Acompound of claim 15, wherein R¹¹ is —(CH₂)_(t)thiazolyl, wherein t isan integer from 0 to 6, said —(CH₂)_(t)thiazolyl is optionallysubstituted by 1 to 5 R⁵ groups.
 17. A compound of claim 1, wherein R¹is a group of the formula

wherein X² is —S— or —N(R⁶)—, X³ is N or CH, the dashed line in formula3 represents an optional double bond, and the above R¹ groups offormulas 3 and 5 are optionally substituted by 1 to 5 R⁵ substituentsand the R¹ groups of formulas 4 and 6 are optionally substituted by 1 to3 R⁵ substituents.
 18. A compound of claim 17 wherein R¹ is a group offormula 3 above wherein said group is optionally substituted by 1 to 5R⁵ substituents.
 19. A compound of claim 1 wherein said compound isselected from the group consisting of(3R)-(3-methoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-y1]-methanone;(3S)-(3-Methoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;(3R,4R)-(3,4-Dimethoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;meso-(3,4-Dimethoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;(3S,4S)-(3,4-Dimethoxy-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;(R)-(2-Hydroxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;(S)-(2-Hydroxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;(2R)-(2-Methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;(2S)-(2-Methoxymethyl-pyrrolidin-1-yl)-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-methanone;(R)-[7-(1-Ethyl-2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-(2-methoxymethyl-pyrrolidin-1-yl)-methanone;(2R)-[7-(1,2-Dimethyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-(2-methoxymethyl-pyrrolidin-1-yl)-methanone;(2R)-1-{5-[2-(2-Methoxymethyl-pyrrolidine-1-carbonyl)-thieno[3,2-b]pyridin-7-yloxy]-2-methyl-indol-1-yl}-ethanone;(2R)-[7-(1-Methanesulfonyl-2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-(2-methoxymethyl-pyrrolidin-1-yl)-methanone;2-(3-Methyl-3H-imidazol-4-yl)-7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine;2-(1-Methyl-1H-imidazol-2-yl)-7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridine;2-{2-[7-(2-Methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-4-yl}-propan-2-ol;2-{2-[7-(2-Methyl-quinolin-6-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-4-yl}-propan-2-ol;2-{2-[7-(Quinolin-6-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-4-yl}-propan-2-ol;2-{2-[7-(1-Methyl-5-trifluoromethyl-1H-pyrazol-3-yloxy)-thieno[3,2-b]pyridin-2-yl]thiazol-4-yl}-propan-2-ol;4-Methyl-2-[7-(2-methyl-1H-indol-5-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-(4-methyl-piperazin-1-yl)-methanone;2-Methyl-5-{2-[4-methyl-5-(4-methyl-piperazine-1-carbonyl)-thiazol-2-yl]-thieno[3,2-b]pyridin-7-yloxy}1H-indole-3-carbonitrile;{4-Methyl-2-[7-(5-phenyl-1H-pyrazol-3-yloxy)-thieno[3,2-b]pyridin-2-yl]-thiazol-5-yl}-morpholin-4-yl-methanone;(2-{7-[5-(4-Fluoro-phenyl)-1H-pyrazol-3-yloxy]-thieno[3,2-b]pyridin-2-yl}-4-methyl-thiazol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;2-{7-[5-(4-Methoxy-phenyl)-1H-pyrazol-3-yloxy]-thieno[3,2-b]pyridin-2-yl}-4-methyl-thiazol-5-yl)-(4-methyl-piperazin-1-yl)-methanone;and pharmaceutically acceptable salts and solvates of said compounds.20. A compound of the formula 25 or 26

or a pharmaceutically acceptable salt or solvate thereof, wherein: Z¹ ishalo, —CO₂H, —CONH₂, CSNH₂ and Z² is —OR¹; X is CH; wherein R¹ is C₁–C₆alkyl, —C(O)(C₁–C₆ alkyl), C₆–C₁₀ aryl or 5 to 13 membered heterocyclic,wherein said C₆–C₁₀ aryl and 5 to 13 membered heterocyclic groups areoptionally substituted by 1 to 5 R⁵ substituents; each R⁵ isindependently selected from halo, cyano, nitro, trifluoromethoxy,trifluoromethyl, azido, —C(O)R⁸, —C(O)OR⁸, —OC(O)R⁸, —OC(O)OR⁸,—NR⁶C(O)R⁷, —C(O)NR⁶R⁷, —NR⁶R⁷, —OR⁹, —SO₂NR⁶R⁷, C₁–C₆ alkyl,—(CH₂)_(j)O(CH₂)_(q)NR⁶R⁷, —(CH₂)_(t)O(CH₂)_(q)OR⁹, —(CH₂)_(t)OR⁹,—S(O)_(j)(C₁–C₆ alkyl), —(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to 10membered heterocyclic), —C(O)(CH₂)_(t)(C₆–C₁₀ aryl),—(CH₂)_(t)O(CH₂)_(j)(C₆–C₁₀ aryl), —(CH₂)_(t)O(CH₂)_(q)(5 to 10 memberedheterocyclic), —C(O)(CH₂)_(t)(5 to 10 membered heterocyclic),—(CH₂)_(j)NR⁷(CH₂)_(q)NR⁶R⁷, —(CH₂)_(j)NR⁷CH₂C(O)NR⁶R⁷,—(CH₂)_(j)NR⁷(CH₂)_(q)NR⁹C(O)R⁸, —(CH₂)_(j)NR⁷(CH₂)_(t)O(CH₂)_(q)OR⁹,—(CH₂)_(j)NR⁷(CH₂)_(q)S(O)_(j)(C₁–C₆ alkyl), —(CH₂)_(j)NR⁷(CH₂)_(t)R⁶,—SO₂(CH₂)_(t)(C₆–C₁₀ aryl), and —SO₂(CH₂)_(t)(5 to 10 memberedheterocyclic), wherein j is an integer from 0 to 2, t is an integer from0 to 6, q is an integer from 2 to 6, the —(CH₂)_(q)— and —(CH₂)_(t)—moieties of the foregoing R⁵ groups optionally include a carbon-carbondouble or triple bond where t is an integer between 2 and 6, and thealkyl, aryl and heterocyclic moieties of the foregoing R⁵ groups areoptionally substituted by 1 to 3 substituents independently selectedfrom halo, cyano, nitro, trifluoromethyl, azido, —C(O)R⁸, —C(O)OR⁸,—OC(O)R⁸, —OC(O)OR⁸, —NR⁶C(O)R⁷, —C(O)NR⁶R⁷, —(CH₂)_(t)NR⁶R⁷, C₁–C₆alkyl, —(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to 10 memberedheterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹, and —(CH₂)_(t)OR⁹, wherein t isan integer from 0 to 6 and q is an integer from 2 to 6; each R⁶ and R⁷is independently selected from H, C₁–C₆ alkyl, —(CH₂)_(t)(C₆–C₁₀ aryl),—(CH₂)_(t)(5 to 10 membered heterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹, and—(CH₂)_(t)OR⁹, wherein t is an integer from 0 to 6 and q is an integerfrom 2 to 6, and the alkyl, aryl and heterocyclic moieties of theforegoing R⁶ and R⁷ groups are optionally substituted by 1 to 3substituents independently selected from halo, cyano, nitro,trifluoromethyl, azido, —C(O)R⁸, —C(O)OR⁸, —CO(O)R⁸, —OC(O)OR⁸,—NR⁹C(O)R¹⁰, —C(O)NR⁹R¹⁰, —NR⁹R¹⁰, C₁–C₆ alkyl, —(CH₂)_(t)(C₆–C₁₀ aryl),—(CH₂)_(t)(5 to 10 membered heterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹, and—(CH₂)_(t)OR⁹, wherein t is an integer from 0 to 6 and q is an integerfrom 2 to 6, with the proviso that where R⁶ and R⁷ are both attached tothe same nitrogen, then R⁶ and R⁷ are not both bonded to the nitrogendirectly through an oxygen; each R⁸ is independently selected from H,C₁–C₁₀ alkyl, —(CH₂)_(t)(C₆–C₁₀ aryl), and —(CH₂)_(t)(5 to 10 memberedheterocyclic), wherein t is an integer from 0 to 6; each R⁹ and R¹⁰ isindependently selected from H and C₁–C₆ alkyl; and R¹¹ is H, C₁–C₆alkyl, —C(O)NR¹²R¹³, —C(O)(C₆–C₁₀ aryl), —(CH₂)_(t)(C₆–C₁₀ aryl),—(CH₂)_(t)(5 to 10 membered heterocyclic), —(CH₂)_(t)NR¹²R¹³,—SO₂NR¹²R¹³ and —CO₂R¹², wherein t is an integer from 0 to 6, whereinsaid R¹¹ groups C₁–C₆ alkyl, —C(O)(C₆–C₁₀ aryl), —(CH₂)_(t)(C₆–C₁₀aryl), and —(CH₂)_(t)(5 to 10 membered heterocyclic) are optionallysubstituted by 1 to 5 R⁵ groups, and wherein each R¹² and R¹³ isindependently selected from H, C₁–C₆ alkyl, —(CH₂)_(t)(C₃–C₁₀cycloalkyl), —(CH₂)_(t)(C₆–C₁₀ aryl), —(CH₂)_(t)(5 to 10 memberedheterocyclic), —(CH₂)_(t)O(CH₂)_(q)OR⁹, —(CH₂)_(t)OR⁹, q is an integerfrom 2 to 6, and the alkyl, aryl and heterocyclic moieties of theforegoing R¹² and R¹³ groups are optionally substituted by 1 to 3substituents independently selected from R⁵ or R¹² and R¹³ takentogether with the nitrogen to which they are attached to form a C₅–C₉azabicyclic, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, isoquinolinyl, ordihydroisoquinolinyl ring, wherein said C₅–C₉ azabicyclic, aziridinyl,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl,thiomorpholinyl, isoquinolinyl, or dihydroisoquinolinyl ring areoptionally substituted by 1 to 5 R⁵ substituents, with the proviso R¹²and R¹³ are not both bonded to the nitrogen directly through an oxygen.21. A pharmaceutical composition which comprises a therapeuticallyeffective amount of a compound of claim 1 and a pharmaceuticallyacceptable carrier.